The kidney as an endocrine organ involved in the function of vitamin D.

Vitamin D3 must be metabilically altered first in the liver to 25-hydroxyvitamin D3 (25 OH-D3) and subsequently in the kidney to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) before it can function. Because 1,25-(OH)2D3 is formed in the kidney and acts in intestine and bone to elevate serum calcium and phosphate concentrations, it can be considered a hormone. The production of 1,25-(OH)2D3 is feedback regulated either directly or indirectly by serum calcium and serum phosphate concentrations. The hypocalcemic regulation is mediated by the parathyroid glands. The hypophosphatemic stimulus, however, does not involve either the parathyroid or thyroid glands. Under conditions whereby the synthesis of 1,25-(OH)2D3 is repressed, 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3 is formed. This metabolite can be converted further to 1,24,25-trihydroxyvitamin D3 (1,24,25-(OH)3D3), which stimulate intestinal calcium transport but not bone calcium mobilization or phosphate transport reactions. A number of vitamin D-resistant bone diseases may be related to defective vitamin D metabolism. For example, bone disease related to choric renal failure likely results from defective formation of 1,25-(OH)2D3 in the kidney. Treatment of this disease with intravenously administered 1,25-(OH)2D3 is effective in correcting the bone lesions. 1Alpha-hydroxyvitamin D3 (1alpha-OH-D3), a new synthetic analog of 1,25-(OH)2D3 which is less expensive to produce than 1,25-(OH)2D3, is effective in anephric animals and may have several advantages over 1,25-(OH)2D3 in treating bone diseases.

Regulation of the tubular transport of phosphate in the rat: role of parathyroid hormone and 1,25-dihydroxyvitamin D3.

The reduced capability of the tubular Pi transport to adapt to a high Pi diet in TPTX rats can be normalized by physiological doses of 1,25-(OH)2D3. This suggests that the chronic consequence of a lack of PTH could be due, at least in part, to the reduced production of 1,25-(OH)2D3. The mechanism of Pi adaptation appears to be the most important regulator of Pi excretion in the growing rats, since it can markedly alter the acute phosphaturic response to parathyroid hormone.

The enterohepatic physiology of 24,25-dihydroxyvitamin D3.

Products of intravenously administered [3H]24,25-dihydroxyvitamin D3 are excreted in the bile of normocalcemic, vitamin D-replete rats. Within 3 and 24 hr, 7.3% +/- 1.4 and 18.5% +/- 1.4 (mean +/- S.D.) of the administered dose appears in the bile. Three hours after the instillation of the biliary products of [3H]24,25-dihydroxyvitamin D3 into the duodena of other rats. 7.6% +/- 2.05 of the administered dose appears in newly secreted bile; at 24 hr 21.1% +/- 7.8 of the instilled dose is present in newly secreted bile. These data suggest that products of 24,25-dihydroxyvitamin D3 are excreted in bile and undergo an enterohepatic circulation. The metabolites of 24,25-dihydroxyvitamin D3 excreted in bile are much more polar than the parent sterol as assessed by silicic acid chromatography and by high-performance liquid chromatographic techniques. The products are retained on DEAE-cellulose in the presence of methanol are eluted upon the addition of acetic acid to the eluting solvent. The data support the existence of a quantitatively important enterohepatic circulation of polar metabolites of [3H]24,25-dihydroxyvitamin E3; disturbances in this metabolic pathway could help explain the pathogenesis of hepatic and intestinal osteodystrophy.

Enterohepatic physiology of 1,25-dihydroxyvitamin D3 metabolites in normal man.

Within 6 hr of the intravenous administration of radiolabeled 1,25(OH)2D3 to five normal vitamin D-replete human subjects, 15.6% of the injected dose appeared in bile as polar metabolites of 1,25(OH)2D3. Of the injected dose, 27% and 7.5% appeared in the feces and urine, respectively, at 24 hr. In another two subjects, biliary radioactivity was sampled at two jejunal sites separated by a distance of 40 cm; a 24.8% decrease in radioactivity over this segment of bowel was noted. These data demonstrate that products of 1,25(OH)2D3 are excreted in normal human bile. Furthermore, these products are reabsorbed as such or as free 1,25(OH)2D3 in the intestine and re-excreted as polar products in bile. Our data suggest that there is an enterohepatic circulation of the products of 1,25(OH)2D3 in normal man.

Absorption and excretion of cholecalciferol and of 25-hydroxycholecalciferol and metabolites in birds.

The absorption and excretion in vivo of cholecalciferol or 25-hydroxycholecalciferol (25-HCC) were determined in chicks (Gallus domesticus) and turkeys (Meleagris gallopavo). The overall net cholecalciferol or 25-HCC absorption in chicks and cholecalciferol in turkey poults was 66.5 +/- 3.3, 74.9 +/- 3.7 and 83.6 +/- 7.1% of the intake, respectively. The absorption of cholecalciferol or 25-HCC in chicks and turkeys occurred at the upper part of the intestine. 25-HCC, esters and non-polar metabolites of cholecalciferol or 25-HCC, and their polar metabolites, were secreted in the duodenum of chicks and turkeys but were partially reabsorbed at the upper part of the jejunum.

[Hormonal regulation of calcium metabolism and regulation of hormone secretion by Ca2+]. / Die hormonale Regulation des Calciumhaushaltes und die Regulation der Hormonausschüttung durch Ca2+.

In a short review the spectacular discoveries in the field of the Ca-homeostasis are delineated. To begin with, the structure and function of parathyroid hormone and of calcitonin are described, whereas the influence of the tocolytica, the catecholamines and glucagon are only touched. Other short chapters deal with the energetic processes during Ca2+ efflux and influx as well as the intracellulare Ca2+-homeostasis. In greater detail the metabolic changes of vitamin D3 and of 1,25 (OH2) D3 in the human organism are described and the action of the latter-hormone in the entire Ca-metabolism is reviewed. With the model of insulin the decisive importance of ca2+ for release of different hormones is demonstrated.

[Recent advances on the "active" vitamin D: 1alpha,25-dihydroxicholecalciferol (author's transl)]. / Recenti acquisizioni sulla vitamina D "attiva": 1alpha,25-diidrossicolecalciferolo

The researches on the mode of action of vitamin D have shown that vitamin D3 in animals is not utilized as such but after Hydrosylation of carbon 25 in the liver and of carbon 1 in the kidney. 1alpha,25-dihdroxycholecalciferol (1alpha,25-(OH)2D3) is the active on two target organis the intestin and bones, acting as a steroid hormone. In the intestin it controls the syntesis of a specific calcium binding protein (CaPB) responsable for calcium absorption. At the bone level it act on the deposition of calcium salts, and whenever necessary on its mobilization. Therefore 1alpha,25(OH)2D3 is active part of the calcium homeostatic system in the organism together with specific hormones such as parathyroid hormone and calcitonin.

Effect of thyroparathyroidectomy of calcium metabolism in rats: role of 1,25-dihydroxyvitamin D3.

Thyroparathyroidectomy (TPTX) decreases plasma calcium, bone formation and resorption, and tubular reabsorption of calcium. It also reduces the production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] which very likely results in the decrease in the intestinal calcium absorption (Vna) observed after TPTX. We have examined whether the influence of TPTX on plasma calcium and bone calcium fluxes could be corrected by doses of 1,25-(OH)2D3 (2 X 13 pmol/day ip), which just normalize Vna. The study was made by calcium balance and 45Ca kinetics in rats receiving a normal supply of vitamin D3. The results show that in TPTX rats physiological doses of 1,25-(OH)2D3 increased plasma calcium and decreased plasma phosphate. Calcium retention was not fully corrected because 1,25-(OH)2D3 increased urinary calcium excretion. The deposition into and the release of calcium from bone were enhanced by 1,25-(OH)2D3 but remained lower than in pair-fed sham-operated animals. Thus, in as much as the diminished renal production of 1,25-(OH)2D3 in TPTX is entirely responsible for the reduced Vna, the decrease in 1,25-(OH)2D3 could only partly explain the effect of thyroparathyroidectomy on bone calcium fluxes.

[Measurements of plasma concentrations of active vitamin D metabolites in children: interest and limit (author's transl)]. / Mesure des taux circulants des métabolites actifs de la vitamine D chez l'enfant. Intérêt et limites.

This study of the three main vitamin D metabolites namely 25-(OH) D, 24, 25-(OH) 2D and 1, 25-(OH) 2D includes (1) a summary of the usual assay techniques, (2) a discussion about the concentrations and the role of these metabolites during the neonatal and childhood periods, (3) a report of the results obtained during the past seven years in our laboratory with comments on the interest and limits of these assays for the diagnosis of different types of rickets.

The calciuria of increased fixed acid production in humans: evidence against a role for parathyroid hormone and 1,25(OH)2-vitamin D.

We measured mineral and acid balances, serum iPTH, urinary cAMP/creatinine, and plasma concentrations of 25OHD and 1,25(OH)2D in 7 healthy adults during control conditions and during increased fixed acid production achieved either by the administration of NH4Cl (N = 3) or by increased dietary protein intake (N = 4). When acid production was increased, the subjects were in positive acid balance and negative Ca balance because of increased urinary Ca excretion. Serum iPTH fell slightly but urinary cAMP and the plasma levels of vitamin D metabolites did not change. W conclude that the accelerated skeletal and urinary losses of Ca that occur when fixed acid production is increased are not contributed to nor compensated for by the parathyroid-vitamin D endocrine systems.

Physiological and therapeutic differences between vitamin D, its metabolites and analogues.

Since several metabolites and analogues of vitamin D have become available, their physiological and therapeutic potential have been studied in various disorders of mineral metabolism, particularly those classically termed vitamin D-resistant. In some instances this resistance appears to be due to defective metabolism of vitamin D or to defective target organ responses, but in others it is not. Although the precise effect of vitamin D or its metabolites on mineralization of bone is still unknown there is some evidence that the metabolites differ in their relative effects on intestine, bone, muscle and parathyroid glands. These differences may eventually have therapeutic value. At present the major advantage of 1alpha-hydroxylated derivatives of vitamin D over other compounds resides in their more rapid onset and reversal of action which makes them much easier and safer to use.

The chemistry and conformational and biological analysis of vitamin D3, its metabolites and analogues.

The chemical properties, stereochemical relationships and solution conformation, as assessed in part by proton NMR spectroscopy, for vitamin D3, its major metabolites [including 1alpha,25-(OH)2D3, its hormonally active form] and a number of A-ring and side chain analogues are evaluated and discussed in relation to their biological activity. In particular the relative ability of many of these seco-steroids to compete both with 25-OHD3 for its chick serum binding protein and 1alpha,25-(OH)2-D3 for its chick intestinal cytosol-chromatin receptor system was quantitated, in vitro. Further, the relative effectiveness of all these metabolites and analogues to mediate in vivo intestinal calcium absorption and bone calcium mobilization was determined. Collectively these chemical and biological studies constitute a "systems analysis" of the various steroid structural parameters both required and tolerated by the multi-stepped endocrine system associated with the biological actions of vitamin D.

[Clinical importance of disorders of vitamin D metabolism]. / Klinische Bedeutung von Störungen des Vitamin-D-Stoffwechsels.

Some aspects of disordered vitamin D metabolism are reviewed. The causes and consequences of diminished blood levels of 25-OH-D3 are discussed. The role of 1,25(OH)2D3 in calcium and phosphorus homeostasis is presented and the diseases associated with alterations of this hormone are described.

The pathophysiology of altered calcium metabolism in rhabdomyolysis-induced acute renal failure. Interactions of parathyroid hormone, 25-hydroxycholecalciferol, and 1,25-dihydroxycholecalciferol.

We studied six oliguric patients with rhabdomyolysis-induced acute renal failure. On admission, all had marked hyperphosphatemia and hypocalcemia associated with low levels of 1,25-dihydroxycholecalciferol [1,25(OH)2D]. During the early polyuric phase, moderate hypercalcemia was accompanied by marked elevations in plasma 1,25(OH)2D and persistent elevations in parathyroid hormone (both amino and carboxy terminals). During the late polyuric phase, the levels of serum calcium and 1,25(OH)2D reverted to normal. Thus, in rhabdomyolysis-induced acute renal failure, the hypocalcemia of the oliguric phase may be secondary to decreased synthesis of 1,25(OH)2D; severe hyperphosphatemia may also have a major role. The hypercalcemia of the polyuric phase may be partly due to increased synthesis of 1,25(OH)2D, resulting from the high parathyroid hormone levels and recovery of renal function.