What's new in vitamin D for the nephrologist?
Neil J. Schroeder and
John Cunningham
Department of Renal Medicine and Transplantation, Royal London Hospital, Whitechapel, London, UK
Correspondence and offprint requests to:
Dr J. Cunningham, Department of Renal Medicine and Transplantation, Royal London Hospital, Whitechapel, London E1 1BB, UK.
Introduction
In this review we discuss some of the clinical implications of progress in our understanding of the action of vitamin D and its derivatives on calcium, phosphate homeostasis and skeletal function in uraemia.
The parathyroid glands synthesize and secrete parathyroid hormone (PTH) in response to low calcium, low 1,25-dihydroxyvitamin D3 (calcitriol), and high phosphate concentrations. The interplay between these elements is complex, operating through several feedback mechanisms. Both PTH and calcitriol regulate circulating calcium and phosphate concentrations through their action on target organs, namely the kidney, bone, and intestine. PTH and calcitriol regulate one another's production, and additionally are both regulated separately by extracellular calcium and phosphate, as schematically illustrated in Figure 1
. The impairment of phosphate excretion and of calcitriol synthesis that accompanies renal insufficiency results in increased parathyroid stimulation from each of the principal modulators, namely decreased calcium, increased phosphate, and decreased calcitriol. This scenario is further complicated by the blunted target organ responsiveness to both PTH and calcitriol in uraemia.

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Fig. 1. The interrelationships between homeostatic hormones. Augmentation and reduction of linked processes/concentrations are depicted as positive (+ve) or negative (-ve) respectively. *These relationships are qualitatively preserved in uraemia with the exception of PTH-driven phosphaturia. The absence of phosphaturia in ESRD results in PTH acting as a phosphataemic hormone, as part of a positive feedback loop with phosphate.
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The vitamin D receptor
Calcitriol mediates its genomic effects through the vitamin D receptor (VDR), which is a member of the steroid/thyroid superfamily of nuclear receptors. Calcitriol binding to VDR results in changes in transcription rates for those genes that contain vitamin D responsive elements (VDREs). There are many other facets to this process, the details of which are beyond the scope of this review. Interested readers are directed to other reviews of this topic [1,2]. Uraemia diminishes the tissue response to calcitriol and this is likely to be due, at least in part, to abnormal regulation and function of the VDR [3]. Down-regulation of VDR content has been demonstrated in the parathyroids of uraemic animals [4]. Uraemic toxins have been shown to decrease the ability of the VDR to bind the VDRE as demonstrated for the osteocalcin gene [5] and it is possible that these effects could be ameliorated by early institution of vitamin D therapies. Experiments in the uraemic rat have shown that administration of either calcitriol or the analogue 22-oxacalcitriol (OCT) can prevent the decrease in VDR content of the parathyroids [6].
Recently, homozygous VDR knockout mice have been generated [7,8]. These animals demonstrate phenotypic characteristics similar to that of clinical hypocalcaemic vitamin D-resistant rickets (HVDRR). When these mice are placed on a `rescue diet', in which mineral ion homeostasis is `normalized', they do not develop hyperparathyroidism or the bone abnormalities observed in untreated animals [9], suggesting that the major consequence of VDR ablation is the impairment of intestinal calcium absorption and mobilization of skeletal calcium.
Studies of vitamin D receptor gene polymorphisms have suggested an influence on bone mineral density. For example, the presence or absence of a cleavage site for the restriction enzyme BsmI in the 7th intron of the VDR gene confers a polymorphism that has been linked to bone mineral density in renal patients [10]. The presence or absence of the restriction site defines a `b' or `B' allele respectively. A relationship between serum intact PTH (iPTH) concentrations and genotypes was found in renal failure patients, with lower iPTH concentrations associated with a BB genotype [11]. However, studies that have tried to evaluate a physiological basis to explain the effect of VDR polymorphisms have so far been unsuccessful [12,13] and it is not yet clear whether these polymorphisms are of use in predicting an individual's responsiveness to calcitriol therapies.
Rapid actions of calcitriol that could not be adequately explained by an effect on gene transcription have been demonstrated. This has led to the postulation of a second vitamin D receptor, located in the plasma membrane, that is able to transduce a signal from calcitriol independent of the genomic pathway (reviewed in [14]). This prompts speculation that the tissue specific selective actions of vitamin D metabolites could be the result of different effects on both the classical genomic (VDR) and non-genomic receptors.
Calcitriol and the parathyroids
PTH synthesis and secretion
Calcitriol suppresses PTH directly by powerfully reducing PTH gene transcription [15], as well as by several other processes (Figure 2
). This repression of PTH transcription is mediated by a negative vitamin D response element (VDRE) in the gene promoter [16]. The effects of calcium on the parathyroids are mediated through a specific calcium sensing receptor (CaR) [17] which, in the rat, may be upregulated by calcitriol [18], although this view is contradicted by others [19]. In contrast to calcitriol, both calcium and phosphate regulate PTH production by post-transcriptional effects on pre-proPTH mRNA [20].
Hyperphosphataemia predicts a poor outcome to vitamin D therapy and new data have shown a direct role for phosphate on PTH secretion [2123]. In intact rat parathyroids incubated in culture, high phosphate (34 mmol/l) concentrations were able to increase PTH secretion 34-fold above basal levels in a normal calcium environment and high phosphate concentrations also blunted the suppressive actions of calcium on PTH secretion in this assay [23]. These data suggest that there is likely to be a mechanism whereby parathyroid cells `sense' and respond to extracellular phosphate, presumably through a cell membrane system that can mediate these signals. A possible candidate is the sodium-dependent phosphate co-transporter identified in rat parathyroid, termed rat PiT-1, which is regulated by calcitriol and shows close homology with the mouse and human PiT-1 type III sodium-phosphate cotransporters [24].
Parathyroid cell proliferation
Although normal parathyroid tissue has a constitutively low basal cell proliferation rate [25], a common feature of chronic renal failure is irreversible parathyroid hyperplasia [26]. The same factors that augment PTH secretion also modulate parathyroid growth, namely low calcium, low calcitriol and high phosphate [21,2729]. Calcitriol is a potent inhibitor of proliferation and promoter of differentiation in many cell types including parathyroid cells [30] and, in a uraemic animal model, calcitriol administration was shown to inhibit parathyroid proliferation [31]. These issues are of great clinical importance in that the dynamics of parathyroid cell turnover are such that hyperplasia can develop quite quickly, whereas apoptosis is exceedingly sloweffectively a one-way ticket.
Calcitriol and the kidney
PTH stimulated renal 1
-hydroxylation of 25-hydroxyvitamin D3 to the active hormone is checked by a feedback inhibition, whereby calcitriol promotes its own degradation directly by suppressing 1
-hydroxylase and stimulating 24-hydroxylase activity, and indirectly by elevating ECF calcium. The 1
-hydroxylase gene has now been characterized and studies of its promoter region have identified positive regulatory regions for PTH and calcitonin and a negative regulatory region for calcitriol [32], confirming earlier functional studies. Similar studies identified two VDREs in the upstream region of the 24-hydroxylase gene [33]. These data further corroborate at a molecular level the well-documented physiological role of calcitriol on these enzymes.
Another potentially important regulatory site has been recently identified. Megalin, a multifunctional clearance receptor located on the luminal surface of proximal convoluted tubule (but not other tubular cells), is responsible for the delivery to the 1
-hydroxylase in the proximal tubule cells of the vitamin D binding protein/25(OH)D3 complex which is filtered through the glomerulus [34]. These findings are of great interest since they contradict the previous assumption that the substrate for renal 1
-hydroxylase was free 25(OH)D3 that diffused from ECF across the baso-lateral membrane into the proximal tubular cell, as well as raising the possibility that decreased GFR of any cause could reduce substrate delivery to the renal 1
-hydroxylase.
The role of calcitriol on calcium and phosphate regulation in the kidney has often been contradictory although most evidence points to conservation. Calcitriol upregulates the mRNA and protein expression of the renal type II sodium-dependent phosphate transporter (NaPi-2) in the rat, increasing phosphate uptake in vitamin D deficient rats [35]. Furthermore, the human NaPi-3 gene, was shown to contain a calcitriol-sensitive VDRE in its promoter region [35], pointing to a possible mechanism of calcitriol-mediated phosphate reabsorption in the kidney. However, in another twist to this puzzle a recently identified phosphate-regulating gene with homology to neutral endopeptidases (PHEX) is also thought to affect calcitriol-mediated phosphate absorption. PHEX, which is responsible for X-linked hypophosphataemic rickets (XLH), is postulated to inactivate a potent, still uncharacterized, circulating factor that has been named `phosphatonin'. Phosphatonin may play an important role in phosphate homeostasis by inhibiting both renal NaPi-2 and the renal 1
-hydroxylase [1].
Calcitriol and the intestine
Pharmacokinetic issues may be importantthe maturation cycle of small-bowel epithelial cells is in the order of 70 h, thereby setting a finite limit on the duration of effect of a pulsed dose of a vitamin D analogue. Such considerations would not apply in, for example, parathyroid or bone cells. The promotion of intestinal calcium transport by calcitriol may be partly non-genomica near instantaneous response has been observed in some studiestranscaltachia [36] and the postulated membrane receptor for calcitriol may be involved in this process. These issues are reviewed in detail elsewhere [37].
Calcitriol, calcitriol derivatives and bone
Both PTH and calcitriol act synergistically to regulate bone turnover through the osteoblast. In healthy bone the remodelling cycle is `plastic' and responds, amongst other things, to calcium and phosphate perturbations, increasing formation or resorption according to physiological demands. Uraemia may affect the ability of bone to respond to such perturbations, partly because of blunted responses to PTH [38]. This blunting is partially corrected by provision of calcitriol and/or restriction of phosphate [39].
Maintenance of normal bone turnover in uraemia is an important goal. New vitamin D analogues and calcimimetics may allow us to achieve profound PTH suppression in a large number of patients, thereby removing a major stimulator of osteoblasts, potentially resulting in adynamic bone disorders. A useful property for a calcitriol surrogate in these circumstances would be to maintain osteoblast function by substituting for the anabolic effect of PTH, while potently suppressing the parathyroid. Few studies have examined this issue specifically, although in one report the analogue 22-oxacalcitriol (OCT) was shown to suppress PTH in the uraemic dog without increasing the risk of adynamic bone disease [40]. We have found that there are differences in the ability of calcitriol analogues to stimulate production of the cytokine interleukin-6 (IL-6) in human osteoblast-like cells (Table 1
). IL-6 is a paracrine factor that mediates osteoblast/osteoclast signalling, and may be important in the recruitment of osteoclast progenitors. Maximum stimulation of IL-6 production was achieved by calcitriol and 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) at fairly high concentrations10-710-9 mol/l, whereas OCT and 1,25-dihydroxydihydrotachysterol2 were maximally active at much lower and therapeutically achievable concentrations10-1110-13 mol/l [41].
Clinical developments
The drawbacks of calcitriol therapy (unwanted hypercalcaemia, hyperphosphataemia, inadequate parathyroid suppression, or parathyroid oversuppression) were tackled first by novel, highly unphysiological regimens of calcitriol administration and more recently with structurally modified calcitriol analogues (Table 2
).
Current therapies
The principal therapies still used are calcitriol and its pro-drug, alfacalcidol. They appear to be equally effective, regardless of dosing regimens. Fischer and Harris [42] found that in haemodialysis patients with 2°HPT there was no difference between intermittent oral or i.v. calcitriol regimens. Similar prospective trials in haemodialysis patients also report that the route of calcitriol administration confers no clinical benefit [43,44]. In another randomized trial examining the efficacy of pulse or daily oral calcitriol administration in CAPD patients, both modalities were equally effective at suppressing PTH [45] despite the higher peak concentrations achieved with the pulse regimen. The evidence from these and other controlled studies support the view that there is probably little or no difference between i.v. and oral administration, although it must be borne in mind that with i.v. injection patient compliance is ensured [46].
New analogues
Many vitamin D analogues have been developed outside the context of renal disease. It was shown in the early 1980s that calcitriol has effects on cell proliferation and differentiation and many analogues have since been found to have much more potent anti-proliferative properties. Many of these new analogues are less calcaemic. For example, the anti-psoriasis drug calcipotriol [47] is `non-calcaemic' because of its rapid catabolism once it penetrates the dermis. Other analogues have been shown to reduce circulating PTH concentrations with only modest effects on serum calcium and no hyperphosphataemia [48], and some of these may find a use in the treatment of hyperparathyroid disorders.
Figure 3
shows where it might be possible for an analogue to differ from calcitriol and therefore potentially vary the response. This may in turn lead to either reduced or enhanced expression of proteins involved in calcium and phosphate homeostasis and/or alter cellular functions.

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Fig. 3. Areas where an analogue may differ from calcitriol in its effect and thereby modify target organ response.
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22-oxacalcitriol (OCT)
OCT was developed in the late 1980s and was shown to suppress PTH secretion and synthesis in vitro and in vivo [49] while eliciting much less calcaemia than calcitriol. This encouraging selectivity of OCT may be the result of differences in action at different target tissues. OCT, in contrast to the sustained action of calcitriol, stimulated only transient intestinal calcium absorption in a rat model [50]. More recent evidence also suggests that the lack of effect of OCT on intestinal Ca-BP9k in the intestine may help to explain the lower calcaemic activity of this agent [51]. However, despite these encouraging data in animal models, clinical studies report that effective PTH suppression is still accompanied by hypercalcaemia in many patients [52]. Careful comparisons with calcitriol and/or alfacalcidol are awaited.
1-alpha-hydroxy vitamin D2
It had been assumed that the metabolism of vitamin D2 and vitamin D3 with, respectively, the ergosterol and cholesterol side-chain structure, led to the formation of similar 1,25-dihydroxyvitamin D metabolites, but recent studies in man have suggested that this may not be the case [53,54]. For example, alfacalcidol (1
-OH-D3) is 25-hydroxylated to form calcitriol, whereas 1
-OH-D2 is metabolized to both 1,25- dihydroxyvitamin D2 and 1,24(S)-dihydroxyvitamin D2. The latter metabolite is a potent antiproliferative agent with minimal calcaemic properties [53,55]. Initial studies in haemodialysis patients have shown the effectiveness of 1
-OH-D2 in suppressing secondary hyperparathyroidism without causing hypercalcaemia and without recourse to adjusting the dose of calcium-based phosphate binders [56]. Early results from a large multicentre trial have also demonstrated the efficacy of this vitamin D metabolite in reducing severe hyperparathyroidism [57] but, as with OCT, comparisons with calcitriol or alfacalcidol are still awaited.
Paricalcitol
Paricalcitol (19-nor-1,25-dihydroxyvitamin D2) has also shown encouraging results as a calcitriol alternative. This compound was found to suppress parathyroid gland secretion and growth in the uraemic rat model [58,59]. Of interest was an observed lack of intestinal VDR upregulation that was seen in the calcitriol-treated group [59]. This lack of effect in the intestine may account for the reduced calcaemic and phosphataemic action of this analogue in that model. In recently published clinical studies, paricalcitol was found to have good PTH suppression with very few and only transient increases in serum calcium in haemodialysis patients [60,61]. However, preliminary reports of comparisons with calcitriol suggest that there is probably little difference between paricalcitol and calcitriol in haemodialysis patients.
Falecalcitriol
This fluorinated calcitriol analogue has been compared with alfacalcidol [62] and in a crossover study demonstrated better PTH suppression, but also more hypercalcaemia than alfacalcidol.
Summary
Our current understanding of the actions of calcitriol on mineral ion homeostasis have been much improved by recent insights at the molecular level. The correction of calcitriol lack in renal disease is undoubtedly beneficial in the prevention of both parathyroid hyperplasia and maintenance of bone integrity, and with respect to hyperplasia it is clear that prevention is essentialcure of established hyperplasia often requires surgery. There is no convincing superiority of any particular regimen or dose schedule of the currently available medications. Although some new analogues appear to have better therapeutic potential in experimental settings, this has not been carried over to the clinical arena where the new metabolites have yet to be shown to have a useful edge over calcitriol and alfacalcidol. Clarification of the reason for the disparate results between animal experimental work (good PTH suppression without calcaemia and phosphataemia) and the clinical studies (significant calcaemic effects reminiscent of alfacalcidol and calcitriol) is important, as is refinement of the dosing regimens for the newer analogues.
Acknowledgments
N. J. Schroeder was supported by grants from the National Kidney Research Fund and The Royal London Hospital Special Trustees.
References
-
Haussler MR, Whitfield GK, Haussler CA et al. The nuclear vitamin D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 1998; 13: 325349[ISI][Medline]
-
Brown AJ. Regulation of vitamin D action. Nephrol Dial Transplant 1999; 14: 1116[Free Full Text]
-
Szabo A, Ritz E, Schmidt-Gayk H, Reichel H. Abnormal expression and regulation of vitamin D receptor in experimental uremia. Nephron 1996; 73: 619628[ISI][Medline]
-
Brown AJ, Dusso A, Lopez-Hilker S, Lewis-Finch J, Grooms P, Slatopolsky E. 1,25(OH)2D receptors are decreased in parathyroid glands form chronically uremic dogs. Kidney Int 1989; 35: 1923[ISI][Medline]
-
Patel SR, Ke HQ, Vanholder R, Koenig RJ, Hsu CH. Inhibition of calcitriol receptor binding to vitamin D response elements by uremic toxins. J Clin Invest 1995; 96: 5059[ISI][Medline]
-
Denda M, Finch J, Brown AJ, Nishii Y, Kubodera N, Slatopolsky E. 1,25-dihydroxyvitamin D3 and 22-oxacalcitriol prevent the decrease in vitamin D receptor content in the parathyroid gland of uremic rats. Kidney Int 1996; 50: 3439[ISI][Medline]
-
Yoshizawa T, Handa Y, Uematsu Y et al. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nature Genet 1997; 16: 391396[ISI][Medline]
-
Li YC, Pirro AE, Amling M et al. Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia. Proc Natl Acad Sci 1997; 94: 98319835[Abstract/Free Full Text]
-
Li YC, Amling M, Pirro AE et al. Normalisation of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. Endocrinology 1998; 139: 43914396[Abstract/Free Full Text]
-
Torres A, Salido E. Vitamin D receptor genotype: its role in bone mass and turnover in non-renal and renal patients. Nephrol Dial Transplant 1997; 12: 18111812[Free Full Text]
-
Fernandez E, Fibla J. Betriu A, Pilulats JM, Almirall J, Montoliu J. Association between vitamin D receptor polymorphisms and relative hypoparathyroidism in patients with chronic renal failure. J Am Soc Nephrol 1997; 8: 15461552[Abstract]
-
Kinyamu HK, Gallagher JC, Knezetic JA, DeLuca HF, Prahl JM, Lanspa SJ. Effect of vitamin D receptor genotypes on calcium absorption, duodenal vitamin D receptor concentration, and serum 1,25-dihyroxyvitamin D levels in normal women. Calcif Tissue Int 1997; 60: 491495[ISI][Medline]
-
Gross C, Krishnan AV, Malloy PJ, Eccleshall TR, Zhoa X-Y, Feldman D. The vitamin D gene start codon polymorphism: A functional analysis of FokI variants. J Bone Miner Res 1998; 13: 16911699[ISI][Medline]
-
Norman AW. Receptors for 1
,25(OH)2D3: Past, present and future. J Bone Miner Res 1998; 13: 13601369[ISI][Medline]
-
Silver J, Naveh-Many T, Mayer H, Schmeizer HJ, Popovtzer MM. Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 1986; 78: 12961301[ISI][Medline]
-
DeMay MB, Kiernan MS, DeLuca HF, Kronenberg HM. Sequences in the human parathyroid hormone gene that bind the 1,25-dihydroxyvitamin D3 receptor and mediate transcriptional repression in response 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci 1992; 89: 80978101[Abstract]
-
Brown EM, Pollack M, Riccardi D, Hebert SC. Cloning and characterisation of an extracellular Ca2+-sensing receptor from parathyroid and kidney: new insights into the pathophysiology and pathology of calcium metabolism. Nephrol Dial Transplant 1994; 9: 17031706[ISI][Medline]
-
Brown AJ, Zhong M, Finch J et al. Rat calcium-sensing receptor is regulated by vitamin D but not calcium. Am J Physiol 1996; 270(3 Pt 2): F454460[Abstract/Free Full Text]
-
Rogers KV, Dunn CK, Conklin RL et al. Calcium receptor messenger ribonucleic acid levels in the parathyroid gland are not regulated by plasma calcium or 1,25-dihydroxyvitamin D3. Endocrinology 1995; 136: 499504[Abstract]
-
Moallem E, Kilav R, Silver J, Naveh-Many T. RNA-protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J Biol Chem 1998; 273: 52535259[Abstract/Free Full Text]
-
Silver J. Sela SB. Naveh-Many T. Regulation of parathyroid cell proliferation. Curr Opin Nephrol Hypertens 1997; 6: 321326[ISI][Medline]
-
Slatopolsky E, Finch J, Denda M et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996; 97: 25342540[Abstract/Free Full Text]
-
Almaden Y, Canalejo A, Hernandez A et al. Direct effect of phosphorus on PTH secretion from whole rat parathyroid glands in vitro. J Bone Miner Res 1996; 11: 970976[ISI][Medline]
-
Tatsumi S, Segawa H, Morita K et al. Molecular cloning and hormonal regulation of PiT-1, a sodium-dependent phosphate cotransporter from rat parathyroid glands. Endocrinology 1998; 139: 16921699[Abstract/Free Full Text]
-
Wang Q, Palnitkar S, Parfitt AM. The basal rate of cell proliferation in normal human parathyroid tissue: implications for the pathogenesis hyperparathyroidism. Clin Endocrinol 1997; 46: 343349[ISI][Medline]
-
Parfitt AM. The hyperparathyroidism of chronic renal failure: A disorder of growth. Kidney Int 1997; 52: 39[ISI][Medline]
-
Naveh-Many T, Rahamimov R, Livni N, Silver J. Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J Clin Invest 1995; 96: 17861793[ISI][Medline]
-
Wang Q, Paloyan E, Parfitt AM. Phosphate administration increases both size and number of parathyroid cells in adult rats. Calcif Tissue Int 1996; 58: 4044[ISI][Medline]
-
Canalejo A, Hernandez A, Almaden Y et al. The effect of a high phosphorus diet on the parathyroid cell cycle. Nephrol Dial Transplant 1998; 13 [Suppl 3]: 1922[Abstract/Free Full Text]
-
Kremer R, Bolivar I, Goltzman D, Hendy GN. Influence of calcium and 1,25-dihydroxycholecalciferol on proliferation and proto-oncogene expression in primary cultures of bovine parathyroid cells. Endocrinology 1989; 125: 935941[Abstract]
-
Szabo A, Merke J, Beier E, Mall G, Ritz E. 1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. Kidney Int 1989; 35: 10491056[ISI][Medline]
-
Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S. The promoter of the human 25-hydroxyvitamin D3 1alpha-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin and 1alpha,25(OH)2D3. Biochem Biophys Res Commun 1998; 249: 1116[ISI][Medline]
-
Ohyama Y, Ozono K, Uchida M et al. Identification of a vitamin D-responsive element in the 5'-flanking region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J Biol Chem 1994; 269: 1054510550[Abstract/Free Full Text]
-
Nykjaer A, Drayun D, Walter D et al. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 1999; 96: 507515[ISI][Medline]
-
Taketani Y, Segawa H, Chikamori M et al. Regulation of type II renal Na+-dependent inorganic phosphate transporters by 1,25-dihydroxyvitamin D3. Identification of a vitamin D responsive element in the human NaPi-3 gene. J Biol Chem 1998; 273: 1457514581[Abstract/Free Full Text]
-
de Boland AR, Norman AW. Evidence for involvement of protein kinase C and cyclic monophosphate-dependent protein kinase in the 1,25-dihydroxyvitamin D3-mediated rapid stimulation of intestinal calcium transport (transcaltachia). Endocrinology 1990; 127: 3945[Abstract]
-
Norman AW. Rapid biological response mediated by 1
,25-dihydroxyvitamin D: A case study of transcaltachia (rapid hormonal stimulation of intestinal calcium transport). In: Feldman D., Glorieux F.H., Pike J.W. (eds). Vitamin D. Academic Press, San Diego 1997; 233256
-
Drüeke TB. Abnormal skeletal response to parathyroid hormone and the expression of its receptor in chronic uremia. Pediatr Nephrol 1996; 10: 348350[ISI][Medline]
-
Cunningham J. Parathyroid pathophysiology in uraemia. Nephrol Dial Transplant 1996; 11 [Suppl 3]: 106110[ISI][Medline]
-
Monier Faugere MC, Geng ZP, Friedler RM et al. 22-Oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. Kidney Int 1999; 55: 821832[ISI][Medline]
-
McIntyre CW, Schroeder NJ, Burrin JM, Cunningham J. Effects of new analogues of vitamin D on bone cells: implications for treatment of uraemic bone disease. Kidney Int 1999; 55: 500511[ISI][Medline]
-
Fisher ER, Harris DCH. Comparison of intermittent oral and intravenous calcitriol in hemodialysis patients with secondary hyperparathyroidism. Clin Nephrol 1993; 40: 216220[ISI][Medline]
-
Levine BS, Song M. Pharmacokinetics and efficacy of pulse oral versus intravenous calcitriol in hemodialysis patients. J Am Soc Nephrol 1996; 7: 488496[Abstract]
-
Bacchini G, Fabrizi F, Pontoriero G, Marcelli D, Filippo SD, Locatelli F. `Pulse-oral' versus intravenous calcitriol therapy in chronic hemodialysis patientsA prospective and randomized study. Nephron 1997; 77: 267272[ISI][Medline]
-
Moe SM, Kraus MA, Gassensmith CM, Fineberg NS, Gannon FH, Peacock M. Safety and efficacy of pulse and daily calcitriol in patients on CAPD: a randomized trial. Nephrol Dial Transplant 1998; 13: 12341241[Abstract]
-
Coburn JW, Frazao J. Calcitriol in the management of renal osteodystrophy. Semin Dial 1996; 9: 316326[ISI]
-
Calverley MC. Synthesis of MC903, a biologically active vitamin D metabolite analog. Tetrahedron 1987; 43, 46094619[ISI]
-
Hruby M, Ureña P, Mannstadt M, Schmitt F, Lacour B, Drüeke TB. Effects of new vitamin D analogues on parathyroid function in chronically uraemic rats with secondary hyperparathyroidism. Nephrol Dial Transplant 1996; 11: 17811786[Abstract]
-
Brown A, Ritter CR, Finch JL et al. The noncalcemic analogue of vitamin D, 22-oxacalcitriol, suppresses parathyroid hormone synthesis and secretion. J Clin Invest 1989; 84: 728732[ISI][Medline]
-
Brown AJ, Finch J, Marvin G et al. The mechanism for the disparate actions of calcitriol and 22-oxacalcitriol in the intestine. Endocrinology 1993; 133: 11581164[Abstract]
-
Ichikawa F, Hirata M, Endo K et al. Attenuated up-regulation of vitamin D-dependent calcium-binding proteins by 22-oxa-1,25-dihydroxyvitamin D3 in uremic rats: A possible mechanism for less-calcemic action. Nephrology 1998; 4: 391395[ISI]
-
Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E, Slatopolsky E. Effect of 22-oxacalcitriol on hyperparathyroidism of dialysis patients: results of a preliminary study. Nephrol Dial Transplant 1996; 11 [Suppl 3]: 121124[ISI][Medline]
-
Knutson JC, Hollis BW, LeVan L, Valliere C, Gould K, Bishop C. Metabolism of 1
-hydroxyvitamin D2 to activated dihydroxyvitamin D2 metabolites decreases endogenous 1
,25-dihydroxyvitamin D3 in rats and monkeys. Endocrinology 1995; 136: 47494753[Abstract]
-
Mawer EB, Jones G, Davies M et al. Unique 24-hydroxylated metabolites represent a significant pathway of metabolism of vitamin D2 in humans: 24-hydroxyvitamin D2 and 1,24-dihydroxyvitamin D2 detectable in human serum. J Clin Endocrinol Metab 1998; 83: 21562166[Abstract/Free Full Text]
-
Knutson JC, LeVan LW, Valliere CR, Bishop CW. Pharmacokinetics and systemic effect on calcium homeostasis of 1
,24(S)-dihydroxyvitamin D2 in rats. Comparison with 1
,25-dihydroxyvitamin D2, calcitriol and calcipotriol. Biochem Pharmacol 1997; 53: 829837[ISI][Medline]
-
Tan AU Jr, Levine BS, Mazess RB et al. Effective suppression of parathyroid hormone by 1
-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int 1997; 51: 317323[ISI][Medline]
-
Frazao JM, Chesney RW, Coburn JW. Intermittent oral 1-alpha-hydroxyvitamin D2 is effective and safe for the suppression of secondary hyperparathyroidism in haemodialysis patients. Nephrol Dial Transplant 1998; 13: 6872[Abstract/Free Full Text]
-
Slatopolsky E, Finch J, Ritter CR et al. A new analog of calcitriol, 19-nor-1,25(OH)2D2, suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis 1995; 26: 852860[ISI][Medline]
-
Takahashi F, Finch J, Denda M, Dusso A, Brown A, Slatopolsky E. A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis 1997; 30: 105112[ISI][Medline]
-
Martin KJ, González EA, Gellens M, Hamm JL, Abboud H, Lindberg J. 19-Nor-1-
-25-Dihydroxyvitamin D2 (paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol 1998; 9: 14271432[Abstract]
-
Llach F, Keshav G, Goldblat MV et al. Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2. Am J Kidney Dis 1998; 32: [Suppl 2], S48S54[ISI][Medline]
-
Akiba T, Marumo F, Owada A et al. Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism. Am J Kidney Dis 1998; 32: 238246[ISI][Medline]