A deficit of calcitriol synthesis may not be the initial factor in the pathogenesis of secondary hyperparathyroidism

Martínez, Isabel; Saracho, Ramón; Montenegro, Jesús Lechuga; Llach, Francisco

doi:10.1093/ndt/11.supp3.22

Cited by 72 publications

(44 citation statements)

References 18 publications

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“…A prevalent explanation for low calcitriol levels in CKD is that with insufficient renal mass, there is decreased renal 1␣-hydroxylase activity imposing a block in the vitamin D synthetic pathway. However, the results of this study, which corroborate data from previous studies (6,8), suggest that significant reductions in calcitriol levels occur early in CKD. Indeed, we have shown that reductions in serum calcitriol to subnormal levels occur with greater frequency and earlier in the course of CKD than the development of anemia, another endocrine complication of CKD that is thought to reflect insufficient renal mass.…”

Section: Discussionsupporting

confidence: 91%

“…Traditionally, the progressive reduction in calcitriol levels has been attributed to insufficient renal 1␣-hydroxylase activity as a result of the concomitant decline in renal mass along with a functional inhibition of the enzyme by hyperphosphatemia (7). However, although these factors likely play an important role in advanced CKD, the observation that calcitriol levels begin to decline long before the development of hyperphosphatemia (4,8) suggests that additional pathophysiologic mechanisms likely contribute.…”

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confidence: 99%

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Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease

Gutiérrez¹,

Isakova²,

Rhee³

et al. 2005

Journal of the American Society of Nephrology

798

637

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Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1␣-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D 3 , calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe PO4 ) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe PO4 was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe PO4 . Increased FGF-23 and decreased 25(OH)D 3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe PO4 , and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease

Gutiérrez¹,

Isakova²,

Rhee³

et al. 2005

Journal of the American Society of Nephrology

798

637

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“…CKD-MBD, with fi ve stages defi ned by decreasing glomerular fi ltration rate (GFR), is well known to be accompanied by a gradual fall in serum 1,25-(OH) 2 D 3 (normal range, 20-60 pg/ml), widely assumed to be due to a gradual decline in CYP27B1 activity ( 102 ). Whether this is in turn due to loss of the CYP27B1 protein caused by renal damage is debatable.…”

Section: Other Potential 25-hydroxylasesmentioning

confidence: 99%

Cytochrome P450-mediated metabolism of vitamin D

Jones

Prosser

Kaufmann

2014

Journal of Lipid Research

369

292

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signal transduction system, the DBP-knockout mouse is normocalcemic and exhibits normal tissue distribution of vitamin D metabolites and vitamin D action despite exhibiting very low blood levels of 1,25-(OH) 2 D 3 . This unexpected phenotype raised questions about DBP's exact role: essential transporter or buffer against toxicity ( 7,8 ). Work performed on the 25-hydroxylases over the past four decades in humans and a variety of animal species has revealed that several cytochrome P450 enzymes 2 (CYP), such as CYP2R1, CYP27A1, CYP3A4, CYP2D25, and perhaps others, are capable of 25-hydroxylation of vitamin D 3 or related compounds. These CYPs can be referred to as vitamin D 3 -25-hydroxylases, and it is CYP2R1 that is emerging as the physiologically relevant enzyme ( 9 ). On the other hand, there is no ambiguity over the second step of 1 ␣ -hydroxylation or the 25-OH-D 3 -1 ␣ -hydroxylase enzyme responsible, which is carried by a single cytochrome P450 2 named CYP27B1 ( 10-12 ). The inactivation of vitamin D is carried out by the mitochondrial enzyme, 25-hydroxyvitamin D 3 -24-hydroxylase, fi rst described in the early 1970s and initially believed to be involved solely in the renal 24-hydroxylation of 25-OH-D 3 ( 13 ). Work performed over the last 35 years has shown that 24-hydroxylase enzyme activity is the result of CYP24A1 ( 5, 14 ). CYP24A1 catalyzes the conversion of both 25-OH-D 3 and 1,25-(OH) 2 D 3 into a series of 24-and 23-hydroxylated products targeted for excretion along well-established pathways culminating in the water-soluble biliary metabolite calcitroic acid or a 26,23-lactone.This article assembles the most currently pertinent literature on the activating and inactivating enzymes of vitamin D metabolism and highlights protein structure and enzymatic properties, crystal structures, gene organization, and The activation of vitamin D 3 is accomplished by sequential steps of 25-hydroxylation to produce the main circulating form, 25-hydroxyvitamin D (25-OH-D 3 ), followed by 1 ␣ -hydroxylation to the hormonal form, 1 ␣ ,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) ( 1 ) ( Fig. 1 ). The initial step of 25-hydroxylation occurs in the liver ( 2 ), and the second step occurs both in the kidney and extrarenal sites ( 3, 4 ). The fat-soluble vitamin D and its metabolites are transported from one tissue to another on the vitamin D-binding protein (DBP), which shows different affi nity for the individual metabolites ( 5 ). The cell-surface receptor megalin-cubilin is thought to facilitate the endocytosis of a DBP-bound 25-OH-D 3 into a number of cell types, especially kidney cells ( 6 ). While it is widely believed that DBP is an essential component of the vitamin D

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“…After discovering the presence of the VDR in PTGs and that calcitriol regulates parathyroid cell proliferation and PTH synthesis (88,107,110,116), the treatment in CKD patients on dialysis shifted to intravenous injections of calcitriol. Furthermore, the fact that calcitriol levels decrease progressively as renal function declines (72) made it the treatment of choice as hormone replacement therapy. In addition, low levels of calcitriol in CKD are expected to have even lower biological effects, since the binding of activated VDR to the response elements in the DNA is compromised in uremia (89).…”

Section: Present Use Of Vdras In Patients With Ckdmentioning

confidence: 99%

A new role for vitamin D receptor activation in chronic kidney disease

Valdivielso

Cannata-Andía

Coll

et al. 2009

American Journal of Physiology-Renal Physiology

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Valdivielso JM, Cannata-Andía J, Coll B, Fernández E. A new role for vitamin D receptor activation in chronic kidney disease. Am J Physiol Renal Physiol 297: F1502-F1509, 2009. First published July 22, 2009 doi:10.1152/ajprenal.00130.2009.-Vitamin D has proven to be much more than a simple "calcium hormone." The fact that the vitamin D receptor has been found in cells not related to mineral metabolism supports that statement. The interest of nephrologists in vitamin D and its effects beyond mineral metabolism has increased over the last few years, evidencing the importance of this so-called "sunshine hormone." In the present review, we highlight the most recent developments in the traditional use of vitamin D in chronic kidney disease (CKD) patients, namely, the control of secondary hyperparathyroidism (sHPT). Furthermore, we also explore the data available regarding the new possible therapeutic uses of vitamin D for the treatment of other complications present in CKD patients, such as vascular calcification, left ventricular hypertrophy, or proteinuria. Finally, some still scarce but very promising data regarding a possible role of vitamin D in kidney transplant patients also are reviewed. The available data point to a potential beneficial effect of vitamin D in CKD patients beyond the control of mineral metabolism.VITAMIN D IS A STEROID HORMONE that has long been known for its important role in regulating body levels of calcium (Ca) and phosphorus (P) and in mineralization of bone. However, there is an increasing amount of data proving that vitamin D exerts its effects beyond kidney, intestine, and bone (Fig. 1). The active form of vitamin D (calcitriol) mediates its biological effects by binding to the vitamin D receptor (VDR), which then translocates to the nuclei of target cells (for review, see Ref. 47). The VDR is a ligand-activated transcription factor that, after activation, recruits cofactor molecules and binds to specific DNA binding sites to modify the expression of target genes. Ligand-mediated conformational changes of the VDR contribute to specific mechanisms in its signaling cascade. Thus the structural chemical modification of active vitamin D is a powerful tool in discovering new compounds that show selective activation of the VDR. Over the last years, a number of new VDR activators (VDRAs), defined as compounds that can bind to VDR and induce its activation, have been synthesized and used in several diseases, including in patients with CKD. Their potential as new therapeutic agents has boosted this area of research. Moreover, new evidence suggests that VDR polymorphisms may influence the response to VDRAs (125). Present Use of VDRAs in Patients with CKDOne of the main complications in patients with CKD is the development of secondary hyperparathyroidism (sHPT). In the past, the increase in parathyroid gland (PTG) size and parathyroid hormone (PTH) synthesis were attributed to a decrease in circulating Ca. As a result, patients with sHPT were treated with oral vitamin D metabolites to correct ...

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A deficit of calcitriol synthesis may not be the initial factor in the pathogenesis of secondary hyperparathyroidism

Cited by 72 publications

References 18 publications

Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease

Fibroblast Growth Factor-23 Mitigates Hyperphosphatemia but Accentuates Calcitriol Deficiency in Chronic Kidney Disease

Cytochrome P450-mediated metabolism of vitamin D

A new role for vitamin D receptor activation in chronic kidney disease

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