24-25-dihydroxyvitamin-d-3 and Kidney-Failure--Chronic

Deficiency of 1,25-dihydroxyvitamin D [1,25(OH)(2)D] and excessive fibroblast growth factor (FGF23) are suggested to be associated with increased mortality in patients with chronic kidney disease (CKD). Generally, 24-hydroxylation has been considered the first step in the degradation pathway of 1,25(OH)(2)D and 25(OH)D. 24,25-dihydroxyvitamin D [24,25(OH)(2)D] was believed to be a degradation product, with no important biological effects. However, some data have accumulated showing that 24,25(OH)(2)D has biological effects on its own. Under conditions of eucalcemia, the synthesis of 24,25(OH)(2)D is increased, and the synthesis of 1,25(OH)(2)D is decreased. In patients with CKD, both high parathyroid hormone levels, which decrease the activity of enzyme CYP24A1 (24-hydroxylase), and high FGF23 levels, which increase the activity of enzyme CYP24A1, were often detected. However, information about 24,25(OH)(2)D levels in these patients is very limited. Whether compensatory changes in levels of FGF23 and 24,25(OH)(2)D in CKD patients are protective or harmful remain unknown issues. Therefore, more studies are needed to identify the nature of the interactions between these molecules and to fully elucidate their clinical significance.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Renal Dialysis; Vitamin D Deficiency; Vitamins

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

The available data with regard to the use of calcitriol, 1 alpha-hydroxyvitamin D3 (1 alpha-OH D3), and 24,25-dihydroxyvitamin D3 (24,25-[OH]2D3) in the management of chronic renal insufficiency are reviewed. Patients with mild to moderate osteitis fibrosa experience substantial improvement with either calcitriol or 1 alpha-OH D3 therapy. However, few patients experience a reversal to normal in histologic characteristics of bone. The conditions of patients with osteomalacia do not respond to either calcitriol or 1 alpha-OH D3 therapy. The bone lesion appearing in these patients is most likely a toxic effect of aluminum. The prognosis is usually poor, but the conditions of some patients may respond to administration of 24,25-(OH)2D3 together with calcitriol. Preliminary data suggest that use of chelating agents may be beneficial. In this group of patients, 24,25-(OH)2D3 administration together with calcitriol may be beneficial.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Alkaline Phosphatase; Animals; Bone and Bones; Calcitriol; Chelating Agents; Child; Densitometry; Dihydroxycholecalciferols; Drug Therapy, Combination; Humans; Hydroxycholecalciferols; Hypercalcemia; Kidney Failure, Chronic; Magnesium; Osteitis Fibrosa Cystica; Osteomalacia; Parathyroid Hormone; Phosphates; Prognosis; Radiography; Rats; Renal Dialysis

The authors review recent experimental and human data concerning the potential physiological and pathophysiological role of 24,25 (OH)2D3, the dihydroxylated metabolite of vitamin D which is synthetisized with preference over 1,25 (OH)2D3 in organisms that have been replenished with vitamin D. For the major known effects of vitamin D such as stimulation of intestinal absorption and bone resorption of calcium and phosphorus, 24,25 (OH)2D3 is less effective than the 1,25 (OH)2D3 metabolite and consequently of lesser physiological importance. Some recent in vitro experiments have shown, however, that 24,25 (OH)2D3 intervenes in the stimulation of proteoglycan synthesis, inhibition of PTH, vitamin A and heparin induced resorption, whereas 1,25 (OH)2D3 does not. Although there is controversy as to its direct inhibitory effect on secretion of PTH, it seems to act with 1,25 (OH)2D3 to prevent hyperplasia of parathyroids in vitamin D deficient chicken. From a pathophysiological point, the presence of 24,25 (OH)2D3 seems vital to allow normal bone formation and mineralisation and possibly to counteract excessive bone resorption.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Calcium; Chickens; Dihydroxycholecalciferols; Humans; Hypophosphatemia, Familial; Intestinal Absorption; Kidney Failure, Chronic; Parathyroid Hormone

Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking.. An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)2D3 in vitamin D-insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters.. Vitamin D3 and 25(OH)D3 concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D3 change, 8.6 ng/ml [interquartile range, 3.9-25.6 ng/ml] for controls versus 12.6 ng/ml [6.9-41.2 ng/ml] for CKD [P=0.15]; 25(OH)D3 change, 39.2 ng/ml [30.9-47.2 ng/ml] for controls versus 39.9 ng/ml [31.5-44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)2D3 was similar between CKD participants and controls (change, 111.2 pg/ml [64.3-141.6 pg/ml] for controls versus 101.1 pg/ml [74.2-123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)2D3 concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)2D3 after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3-3.5 ng/ml] for controls versus 1.2 ng/ml [0.6-1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)2D3 for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis.. Patients with CKD exhibit an altered ability to increase serum 24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Bone Density Conservation Agents; Calcifediol; Calcitriol; Case-Control Studies; Cholecalciferol; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Vitamin D Deficiency

The effect of combined administration of 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3) and 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) was studied in 24 non-dialyzed patients with chronic renal insufficiency (CRI), matched pairwise as to age, sex, and creatinine clearance (Cr.cl). Low Ca intake had been supplemented beforehand. Then, 1 alpha-(OH)D3 (mean dose 0.55 micrograms daily) was given orally to all patients for 3 months (T0 to T3). Subsequently, patients were assigned randomly to 6 months further treatment either with 1 alpha-(OH)D3 alone (Group A) or with 1 alpha-(OH)D3 plus a high dosage of 24,25-(OH)2D3 (50 micrograms orally, twice weekly) (Group B). Histomorphometry was performed at T0, T3, and T9. In both groups iPTH was equally suppressed, into the lower normal range. Whereas in Group A, serum Ca rose steadily and Cr.cl declined, in Group B both parameters levelled off between T6 and T9. At T9, in Group A the elevated resorption and osteoid indices had normalized markedly, but osteoblasts (Ob.Pm) and mineralizing boundaries (M.Bd) were depressed considerably between T3 and T9. In contrast, in Group B, preservation of Ob.Pm and improved mineralizing activity were observed (M.Bd at T9 > T3 > T0). Resorption indices hardly changed. In the patients with high Ob.Pm at T0, cancellous bone area increased significantly. This was not observed in Group A. Thus, in Group B, osteoblast recruitment appeared maintained and M.Bd appeared normalized. Decline of remodeling toward an adynamic state with an increased risk of hypercalcemia appeared prevented.

Topics: 24,25-Dihydroxyvitamin D 3; Administration, Oral; Adult; Bone Density; Bone Remodeling; Bone Resorption; Calcium; Drug Therapy, Combination; Female; Humans; Hydroxycholecalciferols; Hypercalcemia; Ilium; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis

We measured the serum parathyroid hormone (PTH) levels in 20 patients treated with continuous ambulatory peritoneal dialysis before and after oral treatment with 24,25-dihydroxyvitamin D3- 24,25(OH)2D3. This metabolite was given in addition to existing treatment with 1 alpha-OH-D3 and calcium carbonate. Administration of 24,25(OH)2D3 led to a significant decrease in PTH levels (intact molecule) from 382 +/- (SE) 65 to 245 +/- 54 pg/ml in 9 patients whose initial levels were extremely high (p = 0.01). No side effects were observed. On the average, calcium values were unchanged and within the normal range throughout the study period; however, a few episodes of mild asymptomatic hypercalcemia occurred which responded quickly to reduction of the calcium carbonate dosage. The present study suggests that oral administration of 24,25(OH)2D3 combined with 1 alpha-OH-D3 is safe and capable of suppressing the raised serum PTH levels of end-stage renal disease patients without the danger of significant hypercalcemia.

Topics: 24,25-Dihydroxyvitamin D 3; Administration, Oral; Aged; Calcium Carbonate; Dose-Response Relationship, Drug; Humans; Kidney Failure, Chronic; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis, Continuous Ambulatory

Fifteen patients with dialysis osteomalacia were treated with 24,25-dihydroxyvitamin D3 in dosages up to 10 micrograms per day for two to 24 months. All had previously had no improvement during treatment with calcitriol but had been remarkably susceptible to hypercalcemia. When 24,25-dihydroxyvitamin D3 was given with either calcitriol or dihydrotachysterol, serum calcium levels were significantly lower than during treatment with calcitriol or dihydrotachysterol alone. Eight of nine patients who received combined therapy with 24,25-dihydroxyvitamin D3 and calcitriol for longer than two months had clinical improvement; six patients underwent repeated bone biopsy and showed evidence of improved bone mineralization. Patients who received 24,25-dihydroxyvitamin D3 alone did not improve clinically. Since 24,25-dihydroxyvitamin D3 appears to improve calcium homeostasis and bone mineralization in some patients with severe dialysis osteomalacia when administered with 1-hydroxylated vitamin D metabolites, further controlled studies are warranted.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Alkaline Phosphatase; Biopsy; Bone Resorption; Calcitriol; Calcium; Child, Preschool; Clinical Trials as Topic; Dihydrotachysterol; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteomalacia; Renal Dialysis; Time Factors

Twenty-three patients with end-stage renal failure on maintenance haemodialysis were treated with 1,25-dihydroxy vitamin D3 or 24-25-dihydroxy vitamin D3 for 3-32 months (total 232 patient months). Treatment with 1,25-dihydroxy vitamin D3 was marked by symptomatic, biochemical and histological improvements in the majority of patients. In contrast, treatment with 24,25-dihydroxy vitamin D3 produced no biochemical or histological improvements and such patients developed severe symptomatic bone disease. Successful renal transplantation resulted in rapid improvement in symptoms, biochemistry and bone histology in nine of 10 patients irrespective of whether prior treatment was with 1,25-dihydroxy vitamin D3, 24,25-dihydroxy vitamin D3 or both. During treatment with 1,25-dihydroxy vitamin D3 progressive reduction in dosage was required in the majority of patients because of hypercalcaemia, which was rapidly corrected by stopping treatment for a few days. Hypercalcaemia did not occur until serum alkaline phosphatase (AP) and amino terminal parathyroid hormone (N-PTH) had fallen towards normal. Treatment failure was uncommon in 1,25-dihydroxy vitamin D3-treated patients and was characterized by the early development of hypercalcaemia. Addition of 24,25-dihydroxy vitamin D3 in such patients rendered the hypercalcaemia more manageable but did not lead to any further improvement in biochemistry or bone histology. Treatment with 24,25-dihydroxy vitamin D3 was accompanied by the development of severe symptomatic bone disease in the majority of patients and a characteristic pattern of biochemical abnormalities with hypocalcaemia and rises in AP and N-PTH. Substitution of 1,25-dihydroxy vitamin D3 treatment for 24,25-dihydroxy vitamin D3 in these patients resulted in prompt improvement in clinical, biochemical and histological abnormalities. Successful renal transplantation was accompanied by rapid resolution of clinical, biochemical and histological features of renal osteodystrophy irrespective of whether previous treatment was with 1,25-dihydroxy vitamin D3 or 24,25-dihydroxy vitamin D3. Hypophosphataemia was common in the early months after renal transplantation without evidence of continuing hyperparathyroidism. The studies have confirmed that 1,25-dihydroxy vitamin D3 is effective in controlling clinical, biochemical and histological features of renal osteodystrophy while 24,25-dihydroxy vitamin D3 did not have a useful therapeutic effect in the dose used.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Drug Therapy, Combination; Humans; Hypercalcemia; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Time Factors

Seventeen undialysed adult patients with chronic renal failure took part in a controlled study of the effects of 1,25(OH)2D3 and D3. After a 6-month observation period the patients were allocated at random to two groups for 6 months of treatment with either 1,25(OH)2D3 (mean dose 0.5 microgram daily) or D3 (dose 100 microgram daily). The treatment was then discontinued and the patients were studied for a further 3 months. In the 1,25(OH)2D3 group the mean serum concentration of 1,25(OH)2D rose significantly during treatment, whereas serum concentratins of 25OHD and 24,25(OH)2D remained unchanged. In the D3 group there was a highly significant increase in serum concentrations of 25OHD and 24,25(OH)2D, whereas serum 1,25(OH)2D remained unchanged. There was a significant fall in serum iPTH in both treatment groups. This fall was unrelated to serum calcium in the D3 group unlike the findings in the 1,25(OH)2D3 group. The data support previous experimental evidence that serum iPTH can be suppressed by 24,25(OH)2D3 and suggest that this analogue may be of clinical importance in the treatment of chronic renal failure without inducing hypercalcaemia.

Topics: 24,25-Dihydroxyvitamin D 3; Adolescent; Adult; Calcifediol; Calcitriol; Calcium; Cholecalciferol; Clinical Trials as Topic; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Kidney Failure, Chronic; Male; Parathyroid Hormone

Topics: 24,25-Dihydroxyvitamin D 3; Diabetes Mellitus; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Observational Studies as Topic; Randomized Controlled Trials as Topic

Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.. Cross-sectional study.. 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).. eGFR.. Circulating 24,25(OH)2D3 concentration.. GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.. Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.. Lack of direct pharmacokinetic measurements of vitamin D catabolism.. Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Observational Studies as Topic; Randomized Controlled Trials as Topic; Young Adult

Topics: 24,25-Dihydroxyvitamin D 3; Diabetes Mellitus; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Observational Studies as Topic; Randomized Controlled Trials as Topic

This study compares the effects of 1,25(OH)2D3 and 24,25(OH)2D3 alone or in combination on renal osteodystrophy in rats with chronic renal failure (CRF).. One month subsequent to 5/6 nephrectomy animals were divided into four groups and treated for one or four weeks with either vehicle, 1,25(OH)2D3, 24,25(OH)2D3 or 1,25(OH)2D3 + 24,25(OH)2D3. A sham-operated group with normal renal function matched for age and weight was used as control. At the termination of the study blood chemistry, parathyroid hormone (PTH) level and bone histomorphometry were analyzed.. The main findings were: amelioration of 1,25(OH)2D3-induced hypercalcemia by 24,25(OH)2D3, and similar suppression of PTH by the two metabolites of vitamin D when administered alone or in combination. Bone histomorphometry showed that 1,25(OH)2D3 alone exerts a potent proliferative effect on the osteoblasts but severely depresses their mineralizing capacity in a dose- and time-dependent manner. By contrast, 24,25(OH)2D3 improved the mineralizing activity with only a limited effect on osteoblast proliferation. Addition of 24,25(OH)2D3 potentiated the beneficial effect of 1,25(OH)2D3 on bone-resorbing parameters and corrected the mineralization failure.. Based on the above observations we suggest that the combined treatment with 1,25(OH)2D3 and 24,25(OH)2D3 markedly improves the morphologic and metabolic abnormalities of renal osteodystrophy.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Bone and Bones; Calcitriol; Calcium Channel Agonists; Chronic Kidney Disease-Mineral and Bone Disorder; Drug Therapy, Combination; Kidney Failure, Chronic; Male; Rats

In patients with chronic renal failure (CRF), abnormalities in vitamin D metabolism are known to be present, and several factors could contribute to the abnormalities.. We measured serum levels of three vitamin D metabolites, 1,25(OH)2D, 24, 25(OH)2D and 25(OH)D, and analyzed factors affecting their levels in 76 nondialyzed patients with CRF (serum creatinine> 1.6 and < 9.0 mg/dl), 37 of whom had diabetes mellitus (DM-CRF) and 39 of whom were nondiabetic (nonDM-CRF).. Serum levels of 1,25(OH)2D were positively correlated with estimated creatinine clearance (CCr; r = 0.429; P < 0.0001), and levels of 24,25(OH)2D were weakly correlated with CCr (r = 0.252, P < 0.05); no correlation was noted for 25(OH)D. Serum levels of all three vitamin D metabolites were significantly and positively correlated with serum albumin. Although there were no significant differences in age, sex, estimated CCr, calcium and phosphate between DM-CRF and nonDM-CRF, all three vitamin D metabolites were significantly lower in DM-CRF than in nonDM-CRF. To analyze factors influencing vitamin D metabolite levels, we performed multiple regression analyses. Serum 25(OH)D levels were significantly and independently associated with serum albumin, presence of DM and serum phosphate (R2 = 0.599; P < 0.0001). 24,25(OH)2D levels were significantly and strongly associated with 25(OH)D (beta = 0.772; R2 = 0.446; P < 0.0001). Serum 1,25(OH)2D levels were significantly associated only with estimated CCr (R2 = 0. 409; P < 0.0001).. These results suggest that hypoalbuminemia and the presence of DM independently affect serum 25(OH)D levels, probably via diabetic nephropathy and poor nutritional status associated with diabetes, and that 25(OH)D is actively catalyzed to 24,25(OH)2D in CRF, probably largely via extrarenal 24-hydroxylase. Serum levels of 1,25(OH)2D were significantly affected by the degree of renal failure. Thus, this study indicates that patients with CRF, particularly those with DM, should receive supplements containing the active form of vitamin D prior to dialysis.

Topics: 24,25-Dihydroxyvitamin D 3; Aged; Calcitriol; Creatinine; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Serum Albumin; Vitamin D

The concentrations of (24R)-24,25-dihydroxyvitamin D3[24,25(OH)2D3], 25-hydroxyvitamin D3[25(OH)D3] and its 3-sulphate [25(OH)D3(3)S] in the plasma of healthy subjects, patients with chronic renal failure, patients with climacteric syndrome, pregnant women and foetuses were determined using the enzyme-linked immunosorbent assay and high-performance liquid chromatography. 25(OH)D3(3)S was not detected in about one-third of the plasma samples from patients with chronic renal failure (n = 26). The three metabolites in maternal plasma reached the highest levels in the second trimester of pregnancy followed by a decrease to the values obtained in the first trimester. Older healthy women (age range 44-71 years) showed higher levels of 24,25(OH)2D3 and 25(OH)D3 in the plasma than did young healthy women (age range 21-29 years), whereas no clear difference was observed between the older healthy women and patients with climacteric syndrome. The level of 25(OH)D3(3)S in the plasma was higher in the latter patients than in healthy women.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Calcifediol; Case-Control Studies; Chromatography, High Pressure Liquid; Climacteric; Enzyme-Linked Immunosorbent Assay; Female; Fetus; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pregnancy

A prospective study was made of sequential changes in the metabolism of vitamin D and calcium in 19 allograft recipient during the first year after successful renal transplantation. All but one of the patients received cyclosporine A combined with corticosteroids and azathioprine as immunosuppressive therapy. Shortly after transplantation most patients showed transient hypocalcemia and hypophosphatemia. At the time of transplantation 17 of 19 patients had an elevated plasma intact parathyroid hormone (PTH) level, and at the close of follow-up one in four patients. In six other patients intact PTH was within the reference range, but high in relation to simultaneously measured serum ionized calcium. According, one year after transplantation less than half of the patients showed complete resolution of hyperparathyroidism. The change towards normal in the metabolism of vitamin D began within the first post-transplantation week irrespective of the onset of diuresis. One to two weeks after transplantation 1,25(OH)2D3 and 24,25(OH)2D3 reached the lower limit of normal range. In these renal allograft recipients who received cyclosporine A the long-term values of serum 1,25(OH)2D3 did not differ from those of normal subjects.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Calcifediol; Calcitriol; Calcium; Chronic Kidney Disease-Mineral and Bone Disorder; Creatinine; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Osteocalcin; Parathyroid Hormone; Phosphates; Postoperative Complications; Prospective Studies; Serum Albumin; Vitamin D

We have demonstrated that in renal failure calcitriol degradation is decreased and that administration of vitamin D metabolites increases the degradation. In this study, we measured intestinal 24- and 26-hydroxylase activities and the effects of chronic infusion (7 days) of vitamin D metabolites on these enzymes' activities in rats with experimental renal failure. The enzymatic activity of intestinal 24-hydroxylase, but not 26-hydroxylase, was significantly lower in renal failure rats compared to control sham operated rats. Replacement of calcitriol (3 ng/day) significantly increased 24-hydroxylase activity by 17% in rats with renal failure (P < 0.01), although the activity remained 15% lower than the controls (P < 0.01). Intestinal 26-hydroxylase activity was not lower in renal failure; however, calcitriol treatment increased the activity beyond that of normal controls. In contrast, administration of 25(OH)D3 (600 ng/day) and 24,25(OH)2D3 (1 microgram/day) reduced the conversion of calcitriol to 1,24,25(OH)3D3 by more than 50% and to 1,25,26(OH)3D3 by more than 38%, respectively. We conclude that calcitriol increased its own degradation in renal failure by increasing the enzymatic activities of both 24- and 26-hydroxylase. However, the mechanisms of increased calcitriol degradation by 25(OH)D3 and 24,25(OH)2D3 in renal failure remain unknown.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Calcifediol; Calcitriol; Intestines; Kidney Failure, Chronic; Male; Mixed Function Oxygenases; Rats; Rats, Sprague-Dawley; Vitamin D

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Calcifediol; Calcitriol; Calcium; Creatinine; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Parathyroid Hormone; Phosphates; Reference Values

Previous studies from our laboratory have shown that 24,25(OH)2D3 attenuates the calcemic effect of 1,25(OH)2D3 in rats with reduced renal mass. This study was undertaken to clarify the role of parathyroid hormone in this response. Adult rats (n = 27) with reduced renal mass after parathyroidectomy with an initial plasma calcium of 3.7 +/- 0.1 mEq/liter were divided into four groups: (i) control rats and rats treated with (ii) 24,25(OH)2D3, (iii) 1,25(OH)2D3, and (iv) both 1,25 and 24,25(OH)2D3. After 4 days significant hypercalcemia was seen in PTX animals receiving 1,25(OH)2D3 alone or in combination with 24,25(OH)2D3. Plasma calcium in the combined therapy rats (7.42 +/- 0.22 mEq/liter) was significantly higher than in those treated with 1,25(OH)2D3 alone (6.68 +/- 0.22 mEq/liter, P less than 0.05). After 8 days, plasma calcium was higher in the rats treated with 1,25(OH)2D3 but was of same magnitude in those treated with 1,25(OH)2D3 alone or in combination with 24,25(OH)2D3. In contrast, in a subset of rats (n = 35) with reduced renal mass but intact parathyroid glands similarly treated with the vitamin D metabolites, a blunted calcemic response was seen after the combination of 1,25(OH)2D3 with 25,25(OH)2D3 administration alone. These results show that in rats with reduced renal mass, 24,25(OH)2D3 attenuates the calcemic effect of 1,25(OH)2D3 only in the presence of intact parathyroid glands. The different calcemic responses to 1,25 or combined 1,25 and 24,25(OH)2D3 in intact or parathyroidectomized rats with chronic renal insufficiency may result from different interaction between the vitamin D metabolites and the parathyroid hormone, presumably at the level of bone.

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Calcitriol; Calcium; Kidney; Kidney Failure, Chronic; Male; Parathyroid Hormone; Rats

In a prior study, we reported vitamin D metabolite profiles in the plasma of healthy children. In view of these findings, we investigated these same profiles in children with moderate renal insufficiency. Specimens were obtained in both summer and winter in untreated patients, and before and after treatment for up to 1 year, with either 25(OH)D3 or 1,25(OH)2D3. Mean pretreatment 1,25(OH)2D levels were normal. Levels of 25(OH)D3 were also normal and continued to vary with season. Mean pretreatment 24,25(OH)2D3 levels were significantly lower in patients and, interestingly, did not show the normal seasonal variation. Treatment with 25(OH)D3 resulted in consistent and sustained rises in 25(OH)D3 and 24,25(OH)2D3 levels, but no increase in 1,25(OH)2D levels. After 1,25(OH)2D3 treatment, 25(OH)D3 levels were unchanged but still showed seasonal variation in some patients, suggesting a lack of feedback control by 1,25(OH)2D3. Levels of 24,25(OH)2D3 were not significantly different from baseline values. Levels of 1,25(OH)2D increased initially then dropped to pretreatment levels or lower. Normal 1,25(OH)2D levels and reduced 24,25(OH)2D3 levels with the loss of seasonal variation suggests in our patients that the kidney was able to maintain 1,25(OH)2D levels at the expense of 24,25(OH)2D3 levels, presumably to preserve calcium homeostasis.

Topics: 24,25-Dihydroxyvitamin D 3; Adolescent; Calcifediol; Calcitriol; Child; Child, Preschool; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Seasons; Vitamin D; Vitamin D Deficiency

Twenty-three patients with end-stage renal failure treated by hemodialysis or transplantation were followed for up to 10 years. Sequential full thickness iliac crest bone biopsies were obtained to assess the effects on bone disease of hemodialysis, treatment with 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] and 24,25-dihydroxycholecalciferol [24,25-(OH)2D3] and renal transplantation. The biopsies were analyzed by a computerized histomorphometric technique which allowed accurate measurements of calcified bone and osteoid areas. Serum aluminum and parathyroid hormone concentrations were also monitored. Hemodialysis was associated with a loss of calcified bone and an increase in osteoid areas. The progressive bone loss was arrested but not reversed following treatment with either 1,25-(OH)2D3 or 24,25-(OH)2D3. Osteoid area was unchanged or reduced following treatment with 1,25-(OH)2D3 in all but three patients who had serum aluminum concentrations in excess of 5 mumol/l. 24,25-(OH)2D3 was not effective in reducing osteoid area, and combined treatment with 1,25 and 24,25-(OH)2D3 had no effect beyond that expected with 1,25-(OH)2D3 alone. Bone biopsies showed loss of calcified bone and an increase in osteoid areas one year and more after successful renal transplantation in five patients. Nineteen of the 23 patients developed serum aluminum concentrations greater than 3 mumol/l, probably because of the use of oral aluminum hydroxide as a phosphate binding agent. In these patients serum parathyroid hormone concentrations greater than 600 pg/ml appeared to prevent the development of osteopenia.

Topics: 24,25-Dihydroxyvitamin D 3; Aluminum; Bone and Bones; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Computers; Dihydroxycholecalciferols; Drug Therapy, Combination; Follow-Up Studies; Histological Techniques; Humans; Kidney Failure, Chronic; Kidney Transplantation; Parathyroid Hormone; Renal Dialysis

The serum levels of 25-hydroxycholecalciferol, 24,25-dihydroxycholecalciferol, and 1,25-dihydroxycholecalciferol were measured simultaneously in three groups of adults with different renal function: normal (n = 24), glomerular filtration rate (GFR) greater than 70 ml/min; moderately decreased (n = 15), GFR 5-35 ml/min, and severely decreased (n = 27), GFR less than 5 ml/min. 25-hydroxycholecalciferol was normal in both patient groups with decreased renal function. 1,25-dihydroxycholecalciferol was halved in the group with moderately decreased renal function (p less than 0.01) and severely decreased (almost undetectable) in the group with severely decreased renal function (p less than 0.01). In contrast, 24,25-dihydroxycholecalciferol was normal in the group with moderately decreased renal function and only halved (p less than 0.05) in the group with severely decreased renal function. These findings suggest extrarenal C-24 hydroxylase activity which may be stimulated by decreasing renal function, thus decreasing renal C-24 hydroxylase activity.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Calcifediol; Calcitriol; Dihydroxycholecalciferols; Female; Glomerular Filtration Rate; Humans; Hydroxylation; Kidney; Kidney Failure, Chronic; Male; Middle Aged

We studied the effects of vitamin D metabolites in 29 patients established on chronic hemodialysis. The patients were divided into four groups; one was treated with 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] 0.5 microgram/day, one with 24R,25-dihydroxyvitamin D3 [24,25-(OH)2D3] 10 micrograms/day, and one with both metabolites. The control group was not given vitamin D. Plasma levels of both metabolites were low before treatment. 1,25-(OH)2D3 levels became normal, and 24,25-(OH)2D3 increased to supranormal levels after administration of the corresponding metabolite. Combined treatment produced still higher plasma levels of 24,25-(OH)2D3, suggesting an interaction between the two metabolites. Patients receiving 1,25-(OH)2D3 alone had a greater increase in plasma calcium than those receiving both metabolites. In control patients, hyperparathyroid bone disease worsened over the 10-month observation period. 1,25-(OH)2D3 improved hyperparathyroid bone disease in most patients, as reflected by a reduction in osteoclast and osteoblast numbers, but had no demonstrable effect on mild osteomalacia. 24,25-(OH)2D3 had no significant effect on plasma biochemistry or bone histology, and the effect of combined treatment on histology was similar to that of 1,25-(OH)2D3 alone. Stainable bone aluminum increased slightly in patients given 1,25-(OH)2D3, but aluminum did not affect the response to treatment. We conclude that 1,25-(OH)2D3 is a useful agent in the treatment of renal bone disease, but no therapeutic role is apparent for 24,25-(OH)2D3.

Topics: 24,25-Dihydroxyvitamin D 3; Adult; Aged; Alkaline Phosphatase; Aluminum; Bone Diseases; Calcitriol; Calcium; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Male; Middle Aged; Osteomalacia; Parathyroid Hormone; Phosphorus; Renal Dialysis

The effect of administration of 25 micrograms 24,25-dihydroxyvitamin D3 (24,25(OH)2D) combined with dihydrotachysterol (DHT2) on clinical, radiological, biochemical and bone histological parameters was assessed in ten children on chronic hemodialysis. Eight children had been treated with DHT2 prior to administration of 24,25(OH)2D. Addition of 24,25(OH)2D to the treatment resulted in a decrease in serum calcium values. Therefore higher doses of DHT2 were required to maintain serum-calcium levels between 2.4-2.8 mmol/l. Administration of 24,25(OH)2D did not modify the quality of bone, but histomorphometric investigation did show a significant reduction of the surface percentage of bone trabecula, in the iliac crest, covered with osteoclasts (oc%). Following the administration of 24,25(OH)2D an increase in bone mineralization was shown by X-rays of the wrists and measured by dual photonabsorptiometry. Addition of 24,25(OH)2D to the DHT2 treatment resulted in an increase in serum concentration of 24,25(OH)2D and a decrease in DHT2 levels. The present study suggests that administered 24,25(OH)2D interferes with DHT2 metabolism and increases DHT2 tolerance. Increased bone mineralization may be related to 24,25(OH)2D, a higher dose of DHT2 or both.

Topics: 24,25-Dihydroxyvitamin D 3; Adolescent; Bone and Bones; Calcium; Child; Child, Preschool; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydrotachysterol; Dihydroxycholecalciferols; Drug Therapy, Combination; Female; Humans; Kidney Failure, Chronic; Male; Minerals; Renal Dialysis

The circulating concentrations of 1,25-dihydroxyvitamin D and 24,25-dihydroxyvitamin D are abnormally low in patients with chronic renal failure (CRF). To determine the importance of substrate (25-hydroxyvitamin D) concentration in this phenomenon, five patients with end stage renal disease treated with hemodialysis were given 25-hydroxyvitamin D3 (25-OH-D3) orally for 4 weeks. The serum concentration of 25-OH-D3 increased from a mean (+/- SEM) of 26 +/- 5 ng/ml immediately before therapy to a maximum of 108 +/- 5 ng/ml 4 weeks after beginning administration of 25-OH-D3. The concentrations of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), and 25,26-dihydroxyvitamin D3 (25,26(OH)2D3) increased from 6.6 +/- 0.8 pg/ml, 0.29 +/- 0.10 ng/ml, and 0.36 +/- 0.06 ng/ml, respectively, immediately before 25-OH-D3 administration to 21.7 +/- 2.2 pg/ml, 0.48 +/- 0.09 ng/ml; and 0.78 +/- 0.12 ng/ml, respectively, after 4 weeks of administration of 25-OH-D3. These results suggest that substrate availability may be an important determinant of the circulating concentrations of these metabolites in patients with CRF. It seems possible that the therapeutic effects of 25-OH-D3 administration to the CRF patient may be mediated through the normal actions of 1,25-dihydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and perhaps other metabolites rather than through analog effects of 25-OH-D3.

Topics: 24,25-Dihydroxyvitamin D 3; Administration, Oral; Calcifediol; Calcitriol; Dihydroxycholecalciferols; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Vitamin D

A simple method for extraction, purification and separation of the principal vitamin D metabolites from a single serum sample is described. The method involved extraction of serum with acetonitrile followed by a first purification employing C-18 Sep-pak cartridges eluted with methanol/water and acetonitrile. Final separation before assay was carried out by high pressure liquid chromatography. 1.25-dihydroxy-vitamin D was measured with radioimmunoassay using an antiserum (S11) with high selectivity for 1 alpha-OH function of the hormone at a final dilution of 1:100,000. 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D were measured employing a competitive binding assay with normal rat serum at a final dilution of 1:10,000 as source of binding protein. The mean (+/- SD) serum 1.25-dihydroxy-vitamin D, 24.25-dihydroxy-vitamin D and 25-hydroxy-vitamin D concentrations for a group of healthy subjects were 50.4 +/- 17.3 pg/ml, 2.3 +/- 2.6 ng/ml and 20.8 +/- 12.3 ng/ml, respectively. 1.25-dihydroxy-vitamin D concentrations were low or undetectable in patients on dialysis or with mild renal failure. High 1.25-dihydroxy-vitamin D levels were found in 2 out of 17 patients with primary hyperparathyroidism. In 4 normal subjects treated for two weeks with large doses of 25-hydroxy-vitamin D, serum 25-hydroxy-vitamin D rose from 12.5 ng/ml to 119 ng/ml and from 0.89 ng/ml to 15 ng/ml, respectively; no changes in the 1.25-dihydroxy-vitamin D assay were found.

Topics: 24,25-Dihydroxyvitamin D 3; Calcifediol; Calcitriol; Chromatography, High Pressure Liquid; Dihydroxycholecalciferols; Humans; Hyperparathyroidism; Kidney Failure, Chronic; Methods; Radioimmunoassay; Reference Values; Renal Dialysis

We measured peritoneal losses of the active vitamin D metabolites 1,25(OH)2D3 and 24,25(OH)2D3 in patients receiving continuous ambulatory peritoneal dialysis (CAPD). The serum concentration of 24,25(OH)2D3 was considerably lower than in hemodialysis patients. The serum concentration of 1,25(OH)2D3 was undetectable and rose to levels similar to those in hemodialysis patients only after loading with much higher oral doses of 1-alpha-vitamin D3 than those received by hemodialysis patients. Losses of both metabolites in peritoneal fluid were considerable, averaging approximately 6-8% of the plasma pool per day. These losses lead to low serum levels of these active vitamin D metabolites in CAPD patients, which may be an important factor in exacerbating renal osteodystrophy. Our results indicate the need for increased replacement doses of vitamin D metabolites in CAPD patients.

Topics: 24,25-Dihydroxyvitamin D 3; Ascitic Fluid; Blood Proteins; Calcitriol; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory

Topics: 24,25-Dihydroxyvitamin D 3; 25-Hydroxyvitamin D 2; Calcifediol; Creatinine; Dihydroxycholecalciferols; Ergocalciferols; Humans; Kidney; Kidney Failure, Chronic; Metabolic Clearance Rate; Renal Dialysis

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

Here we report the use of newly developed and established techniques for the determination of plasma levels of a broad spectrum of vitamin D3 metabolites, including vitamin D3 and 25OHD3-lactone, in normal humans, chronic renal failure patients, and anephric subjects. The methodology described consisted of methanol-methylene chloride extraction, Lipidex-5000 chromatography with stepwise gradient elution, normal-phase HPLC with concave gradient elution, and sensitive ligand-binding assays. The results of the study strongly suggest an extrarenal source(s) for 24,25(OH)2D3 and 25,26(OH)2D3 and indicate that both 25OHD3-lactone and 1,25(OH)2D3 may be produced solely in the kidney of the human. Significant reductions or nondetectable plasma levels of vitamin D3 in the renal disease patients may reflect abnormalities in the hepatobiliary-intestinal and/or cutaneous metabolism of vitamin D.

Topics: 24,25-Dihydroxyvitamin D 3; Calcifediol; Calcitriol; Cholecalciferol; Dihydroxycholecalciferols; Humans; Hydroxycholecalciferols; Kidney Failure, Chronic; Methods; Nephrectomy

In forty-two patients with chronic renal failure (CRF), serum concentrations of 25-hydroxy-cholecalciferol (25-OHCC), 24,25-dihydroxy-cholecalciferol (24,25-OH2CC) and 1,25-dihydroxy-cholecalciferol (1,25-OH2CC) were measured before and during intermittent haemodialysis (IHD) and in a few cases also after renal transplantation. 25-OHCC and 24,25-OH2CC were measured by means of a competitive protein binding assay after Sephadex LH20 chromatography and 1,25-OH2CC by means of a radioimmunoassay after Sephadex LH20 and high pressure liquid chromatography (HPLC). In our patients serum values for 25-OHCC and 24,25-OH2CC showed a seasonal fluctuation as in normal individuals. The concentrations in the serum of 24,25-OH2CC and 1,25-OH2CC showed a positive correlation with renal function. With regard to 24,25-OH2CC this correlation was only found for the 24,25-OH2CC:25-OHCC ratio which was used to eliminate the seasonal fluctuation. For both dihydroxylated metabolites subnormal concentrations were found when the creatinine clearance was 40-50 ml/min and lower. It appears that the decrease of the plasma level of these metabolites of Vitamin D precedes (or is concomitant with) the changes in the serum values of calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) and the diminution of the intestinal absorption of Ca. These findings indicate that patients with CRF should be treated at an early stage of the disease with 1 alpha-hydroxy-derivatives of Vitamin D in order to prevent the development of, or to induce the healing of, bone-lesions of renal osteodystrophy.

Topics: 24,25-Dihydroxyvitamin D 3; Adolescent; Adult; Aged; Calcifediol; Calcitriol; Calcium; Dihydroxycholecalciferols; Female; Humans; Hydroxycholecalciferols; Kidney Failure, Chronic; Male; Middle Aged; Phosphorus

Topics: 24,25-Dihydroxyvitamin D 3; Animals; Binding, Competitive; Calcifediol; Calcitriol; Chromatography, Ion Exchange; Dihydroxycholecalciferols; Humans; Hydroxycholecalciferols; Hyperparathyroidism; Hypoparathyroidism; Kidney Failure, Chronic; Radioligand Assay; Rats; Tritium