Extra-renal production of calcitriol in chronic renal failure

Dusso, Adriana; Lopez-Hilker, Silvia; Rapp, Neville S.; Slatopolsky, Eduardo

doi:10.1038/ki.1988.190

Cited by 129 publications

(74 citation statements)

References 64 publications

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“…At any rate, the Vma,, obtained for the hepatic mitochondrial 25(OH)D3 la-hydroxylase is similar to that observed for the pig and rat renal mitochondrial 25(OH)D3 la-hydroxylases (25,32).However, the Km of this hepatic mitochondrial enzyme is a magnitude higher than that observed for the pig and rat renal la-hydroxylases (25,32) or the reconstituted 25(OH)D3 la-hydroxylase from pig renal mitochondria (40). This difference in enzyme Km may account for why serum 1,25(OH)2D3 begins to increase in anephric humans (35), dogs (35), and pigs (36) as circulating 25(OH)D3 approaches pharmacological levels. Thus, under pharmacological conditions, it may be possible for the liver to act as an endocrine organ for 1,25(OH)2D3 production.…”

Section: Identificationmentioning

confidence: 47%

“…The increase in efficiency could result from several factors that remain beyond the scope of this report. It is also important to note that extrarenal production of 1,25(OH)2D3 has been seriously questioned (34), although it is now known to occur under pharmacological conditions and to contribute to circulating 1,25(OH)2D3 (35,36). It is also possible that liver serves to produce 1,25(OH)2D3 in a paracrine, autocrine, and/or intracrine mode and not an endocrine mode.…”

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confidence: 99%

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25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

Proc. Natl. Acad. Sci. U.S.A.

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In vitro studies were performed to assess the ability of hepatic homogenates, mitochondria, and microsomes to la-hydroxylate 25-hydroxyvitamin D3 (25(OH)D3]. Addition of 25(OH)D3 to either hepatic mitochondria or microsomes caused a concentration-dependent increase in the production of 1,25-dihydroxyvitamin D3 [1,25(OH) Because of its inability to achieve substrate saturation, meaningful kinetic parameters could not be calculated for the hepatic microsomal la-hydroxylase. These data demonstrate the liver to be an even more dynamic organ than was previously believed with respect to vitamin D metabolism in that the liver has the potential to produce 1,25(OH)2D3 in situ by at least two separate mechanisms.It is well established that various side chain and/or A-ring hydroxylation reactions are essential for the metabolic activation of vitamin D3 (1, 2). Circulating vitamin D3 first undergoes a hepatic conversion to 25-hydroxyvitamin D3 [25(OH)D3] (3). The hydroxylase enzymes responsible for this conversion are known to be cytochrome P-450 mixed-function oxidases that are NADPH dependent and are located in both hepatic mitochondria (4-6) and microsomes (7,8). Final activation of 25(OH)D3 into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] takes place primarily in the kidney (9). The renal enzyme responsible for this activation, 25(OH)D3 lahydroxylase, is also known to be a cytochrome P450 mixedfunction oxidase that is located solely in the inner mitochondrial membrane (10, 11). In recent years, other tissues have also been shown to be capable of synthesizing 1,25(OH)2D3, including placenta (12), bone cells (13), lymphatic tissue (14), and keratinocytes (15). Compared with the renal 25(OH)D3 la-hydroxylase, very little information is known with respect to the metabolic control of these extrarenal 25(OH)D3 lahydroxylases and essentially no information is available concerning their subcellular distribution.Because of the important role of 1,25(OH)2D3 in various aspects of hepatic function (16-24), the possibility that the liver could synthesize in situ this hormonal form of vitamin D3 was investigated. It is reported here that both hepatic mitochondria and microsomes possess a 25(OH)D3 lahydroxylase in significant amounts. These enzymes differ in some characteristics, but both appear to behave as cytochrome P-450 mixed-function oxidases. MN). Coomassie blue protein assay reagent was purchased from Pierce. Nicotinamide adenine dinucleotide phosphate, isocitrate, N,N'-diphenylethylenediamine (DPED), dithiothreitol, and ethylenediaminetetraacetic acid were purchased from Sigma. All solvents were of HPLC grade and were obtained from Fisher. MATERIALS AND METHODS ReagentsLivers. Livers from 3-month-old castrated male pigs, maintained on stock diet, were obtained at the time of slaughter. The livers were perfused with ice-cold 0.15 M NaCl, minced, and placed in an appropriate volume of ice-cold 50 mM Na2HPO4 (pH 7.4) buffer containing 0.25 M sucrose and 0.5 mM EDTA to provide a 20% (wt/vol) 6009The publication costs of th...

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Section: Identificationmentioning

confidence: 47%

mentioning

confidence: 99%

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

Proc. Natl. Acad. Sci. U.S.A.

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“…In these disorders, macrophage-lineage cells express 25-hydroxyvitamin D-1α-hydroxylase, leading to the overproduction of calcitriol in the extrarenal lesions; the negative feedback of calcitriol is disrupted in these cases (6,12,13). Glucocorticoid treatment is effective because it suppresses the 25-hydroxyvitamin D-1α-hydroxylase expression in macrophage-lineage cells by inhibiting interferon-gamma production, leading to the amelioration of hypercalcemia via a reduction in the level of serum calcitriol (12)(13)(14)(15) In the present case, the serum calcitriol level was relatively high compared to that observed in chronic dialysis patients; the mean serum calcitriol level in anuric hemodialysis patients has been shown to be 5.5±2.4 pg/mL (16). In addition, Rosai-Dorfman cells in the affected lymph nodes exhibited an increased expression of 25-hydroxyvitamin D-1α-hydroxylase, and low-dose prednisolone treatment rapidly improved the patient's hypercalcemia.…”

Section: Discussionmentioning

confidence: 80%

Hypercalcemia Induced by Rosai-Dorfman Disease in a Hemodialysis Patient: Histological Evidence of Extrarenal Calcitriol Overproduction

et al. 2014

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Rosai-Dorfman disease (RDD) is a rare disorder characterized by the proliferation of histiocytes in the sinus of the affected lymph nodes, which leads to massive lymphadenopathy. RDD usually presents as an increased inflammatory response and lymph node swelling. We herein report the case of a hemodialysis patient with a fever, hypercalcemia and increased serum calcitriol level who was histologically diagnosed to have RDD. Immunohistochemistry revealed an increased expression of 1α-hydroxylase by histiocytes in the dilated sinus, indicating the extrarenal overproduction of calcitriol. Treatment with oral prednisolone decreased the serum levels of inflammatory markers and calcitriol, normalized the serum calcium level and mitigated the systemic lymph node enlargement.

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“…67 Supplementation with native vitamin D resulted in an increase in 1,25(OH) 2 D levels even in anephric subjects, suggesting a compensatory activity of the extra-renal system in CKD. 67,68 sHPT treatment with vitamin D prohormone From a pathophysiological aspect, avoidance of vitamin D deficiency early in the course of CKD to prevent or treat mild to moderate sHPT seems reasonable. With progressive CKD and loss of renal 1α-hydroxylase (mainly in stage 5 and 5D), the importance of the supplementation with vitamin D prohormone for systemic effects declines.…”

Section: Impaired Vitamin D Metabolism In Ckdmentioning

confidence: 99%

“…68 There are no convincing data regarding the choice of vitamin D product or the administration route. Altogether, oral repletion seems to be more favorable compared with the intramuscular route in hemodialysis patients.…”

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confidence: 99%

Vitamin D prohormone in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease

Friedl

Zitt

2017

IJNRD

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Secondary hyperparathyroidism (sHPT) represents the adaptive and very often, finally, maladaptive response of the organism to control the disturbed homeostasis of calcium, phosphorus, and vitamin D metabolism caused by declining renal function in chronic kidney disease (CKD). sHPT leads to cardiovascular and extravascular calcifications and is directly linked to an increased risk of cardiovascular morbidity and mortality as well as excess all-cause mortality. Vitamin D plays an important role in the development of sHPT. CKD patients are characterized by a high prevalence of hypovitaminosis D. Supplementation with both vitamin D prohormones cholecalciferol and ergocalciferol enables the achievement and maintenance of a normal vitamin D status when given in adequate doses over an appropriate treatment period. In patients with earlier stages of CKD, sHPT is influenced by and can be successfully treated with vitamin D prohormone supplementation, whereas in patients with very late stages of CKD and those requiring dialysis, treatment with prohormones seems to be of limited efficacy. This review gives an overview of the pathogenesis of sHPT, summarizes vitamin D metabolism, and discusses the existing literature regarding the role of vitamin D prohormone in the treatment of sHPT in patients with CKD. Keywords: cholecalciferol, CKD, CKD-MBD, dialysis, ergocalciferol, SHPT. Pathogenesis of secondary hyperparathyroidism (sHPT) in chronic kidney disease (CKD)sHPT represents the adaptive and very often, finally, maladaptive response of the organism to control the disturbed homeostasis of calcium, phosphorus, and vitamin D metabolism caused by declining renal function in CKD. These disturbances in mineral metabolism lead to vascular 1,2 and valvular 3 calcifications and are directly linked to an increased risk of cardiovascular morbidity and mortality as well as excess all-cause mortality. 4 Apart from extra-skeletal side effects, sHPT also leads to profound alterations in bone metabolism, which become obvious in the different forms of renal osteodystrophy.5 This clinical syndrome encompassing mineral, bone, and cardiovascular abnormalities has been termed "CKD-related mineral and bone disorder" (CKD-MBD).6 sHPT generally develops in CKD stage 3 with an estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m 2 , and its prevalence increases as kidney function declines. 7,8 Initially, it is characterized by normocalcemia with intermittent transient hypocalcemia, fasting normo-or hypophosphatemia, and reduced 1,25(OH) 2 D 3 (calcitriol) concentration, together with increasing levels of fibroblast growth factor 23 (FGF23), a decrease in plasma soluble Klotho, and the development of renal osteodystrophy. [8][9][10][11] These alterations result in increased secretion

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Extra-renal production of calcitriol in chronic renal failure

Cited by 129 publications

References 64 publications

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hypercalcemia Induced by Rosai-Dorfman Disease in a Hemodialysis Patient: Histological Evidence of Extrarenal Calcitriol Overproduction

Vitamin D prohormone in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease

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