Skip Navigation



NDT Advance Access published online on July 20, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn375
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/12/3824    most recent
gfn375v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Noonan, W.
Right arrow Articles by Reinhart, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noonan, W.
Right arrow Articles by Reinhart, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Differential effects of vitamin D receptor activators on aortic calcification and pulse wave velocity in uraemic rats

William Noonan1, Kristin Koch1, Masaki Nakane2, Junli Ma1, Doug Dixon3, Antoinette Bolin1 and Glenn Reinhart4

1 Abbott Laboratories, Abbott Park, IL 2 Pharmaceutical Discovery, Vidagene, Chicago, IL 3 Genusbiosystems, Chicago, IL 4 Department of Safety Pharmacology, Boehringer-Ingelheim, Ridgefield, CT

Correspondence and offprint requests to: Correspondence and offprint requests to: William Noonan, Abbott Laboratories, GPRD, 1029 Sanderling Ct, Antioch, CA, USA. Tel: +1-847-395-2055; Fax: +1-847-395-2055; E-mail: William.Noonan{at}abbott.com



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Vascular calcification is associated with an increase in cardiovascular mortality in stage 5 chronic kidney disease. To determine if vitamin D receptor activators (VDRAs) have differential effects in the pathogenesis of aortic calcification, we assessed the effects of paricalcitol and doxercalciferol in vivo using 5/6 nephrectomized (NX) rats. To quantify the functional consequences of vascular calcification, pulse wave velocity (PWV), an aortic compliance index, was measured.

Methods. NX rats were fed a diet containing 0.9% phosphorous and 0.6% calcium 4 weeks prior to and throughout the study. On Day 0, rats received vehicle or VDRA (0.083, 0.167 and 0.333 µg/kg, i.p.) three times per week for 6 weeks. At Day 0 and Weeks 2 and 6, blood was drawn and PWV was measured by Doppler ultrasound.

Results. VDRAs (0.167 and 0.333 µg/kg) consistently lowered PTH at Weeks 2 and 6. All doses of paricalcitol increased serum calcium at Week 6 but not at Week 2, while the two higher doses of doxercalciferol increased serum calcium at both Weeks 2 and 6. Treatment with paricalcitol (0.333 µg/kg) increased serum phosphorus at Weeks 2 and 6; these changes were not different from those observed in 5/6 NX rats. All doses of doxercalciferol increased serum phosphorus at Week 6. Paricalcitol had no effect on Ca x P; however, the two highest doses of doxercalciferol increased Ca x P at Weeks 2 and 6 above that observed in the 5/6 NX vehicle-treated group. There were no differences in aortic calcium and phosphorus contents at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. However, treatment with the two higher doses of doxercalciferol caused a significant elevation in aortic calcium and phosphorus contents. Measurements of PWV demonstrated differential effects of VDRAs on vascular compliance. Paricalcitol produced no effects on PWV, while the two highest doses of doxercalciferol increased PWV at Week 6.

Conclusions. In uraemic rats with established secondary hyperparathyroidism, we demonstrate differential effects of paricalcitol and doxercalciferol on aortic calcification and PWV, independent of serum Ca, P and Ca x P, suggesting different mechanisms of action between VDRAs.

Keywords: cardiovascular complications; chronic kidney disease; paricalcitol; pulse wave velocity; vascular calcification; vitamin D receptor activator



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Stage 5 chronic kidney disease (CKD) patients experience a high mortality rate due to cardiovascular complications, and studies have shown that arterial damage is an important causative factor in the mortality of this patient population [1–3]. The calcification of cardiovascular tissues is a common complication of stage 5 CKD and is the result of calcium phosphate deposition that can occur in the myocardium, cardiac valves and arteries [4]. Arterial calcification occurs at two distinct sites: intimal calcification, which is associated with atherosclerosis and characterized by lipid accumulation and focal plaque development [5], and medial calcification, which is associated with arteriosclerosis due to age, diabetes and end-stage renal failure [6–9]. Both forms of calcification can result in increased vascular stiffness with reduced vessel elasticity or compliance. Vitamin D receptor activator (VDRA) therapy can be an essential part of effective treatment among stage 5 CKD patients. Calcitriol and VDRAs such as paricalcitol (19-nor-1{alpha},25(OH)2D2) and doxercalciferol (1{alpha}(OH)D2) and calcimimetics are currently used to manage secondary hyperparathyroidism (SHPT) and renal osteodystrophy. Calcitriol not only lowers serum parathyroid hormone (PTH) but also increases serum calcium by stimulating intestinal calcium absorption and bone resorption [10]. The discovery and clinical development of potent selective VDRAs such as paricalcitol, a drug that effectively suppresses PTH levels in CKD without significantly increasing the incidence of hypercalcaemia or hyperphosphataemia, has demonstrated the clear feasibility of achieving effective therapy within a broad therapeutic window [11]. In addition, recent retrospective clinical observations show that VDRAs are associated with improved survival in stage 5 CKD patients in the effectiveness order of paricalcitol > calcitriol > no VDRA therapy, independent of the PTH and calcium levels [12,13]. Additionally, Tentori et al. reported a 20% increased mortality risk for stage 5 CKD patients not receiving intravenous vitamin D compared to those of stage 5 CKD patients that were receiving intravenous vitamin D, again confirming that VDRAs are associated with improved survival in stage 5 CKD [14]. The purpose of this study was to determine if paricalcitol and doxercalciferol have differential effects on aortic calcification and compliance in a rat model of CKD.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Materials
19-nor-1{alpha},25-dihydroxyvitamin D2 (19-nor-1{alpha}, 25(OH)2D2, 19-nor, paricalcitol) and 1{alpha}-hydroxyvitamin D2 (1{alpha}(OH)D2, doxercalciferol) were from Abbott Laboratories. All other reagents were of analytical grade.

Animals
Male, Sprague-Dawley, 5/6 nephrectomized (NX) rats (~200 gm) were obtained from Charles River 1 week after nephrectomy. The nephrectomy was performed using a standard two-step surgical ablation procedure. In phase I of the procedure, the animal's left kidney was exposed after a ventral midline incision. A piece of 2-0 suture was placed around each pole of the kidney at its 1/3 position. The sutures were gently ligated around the kidney and each pole was excised beyond the ligatures. One week later in phase II of the surgical procedure, the right kidney was exposed via an incision on the animal's right flank, and the adrenal gland was gently freed and placed back into the abdominal cavity. The renal blood vessels and ureter were cauterized, and the kidney was removed by transecting the vessels and ureter distal to the cauterized area. Beginning 2 weeks post-nephrectomy, rats were maintained on a high phosphorus diet (0.9% phosphorus and 0.6% calcium) for the duration of the study to induce secondary hyperparathyroidism. On Day 0, SHAM and 5/6 NX rats (n = 7–10 per group) received vehicle (5% EtOH/95% propylene glycol; 0.4 ml/kg; i.p.) or VDRA (paricalcitol or doxercalciferol; 0.083, 0.167 or 0.333 µg/kg; intraperitoneally [15]) three times per week for 41 days (n = 6–10 per group). These doses were chosen based on the fact that lower doses (0.021 and 0.042 µg/kg; i.p.; data not shown) of either compound were not PTH suppressive after 2 or 6 weeks of treatment in this model of CKD. Previous studies have shown that paricalcitol is slightly less potent than doxercalciferol (0.6:1) in suppressing serum PTH, but is 5- to 10-fold less calcaemic and phosphataemic; therefore, dose comparisons should be performed accordingly [16]. On Days 0, 13 and 41, blood was collected (24 h post-dose). On Days 0, 13 and 41 (24 h post-dose), animals were anaesthetized with ketamine (50 mg/kg) and blood was collected via the tail vein for PTH and serum blood chemistry determinations.

Measurement of PTH and serum blood chemistries
Serum PTH was measured using an intact rat PTH ELISA kit (ALPCO/Immutopics, Inc.; Windham, NH, USA). Serum calcium, phosphorus creatinine and BUN concentrations were measured using an Abbott Aeroset (Abbott Park, IL, USA). Blood-ionized calcium was determined using an i-Stat portable clinical analyzer. To minimize bias induced by variance in the disease state, animals were assessed 4 weeks after being placed on a high phosphorus diet (prior to treatment), and the following criteria were applied: serum PTH > 400 pg/mL, serum creatinine 0.8–2.0 mg/dL, total serum calcium > 8.5 mg/dL and serum phosphorus >12 mg/dL.

Assessment of pulse wave velocity using Doppler ultrasound
On Day 0, Weeks 2 and 6, Doppler measurements were used to determine blood flow velocities at the aortic arch and the bifurcation of the abdominal aorta using a 12-MHz linear array probe and a Toshiba Aplio 80 ultrasound (Toshiba America Medical Systems, Tustin, CA, USA). At the end of the experiments, the animals were sacrificed and the distance between the aortic arch and the bifurcation of the abdominal aorta was measured and pulse wave velocity (PWV) was calculated by dividing the separation distance by the difference in arrival times of the velocity pulse timed with respect to the electrocardiogram.

Measurement of calcium and phosphorus contents in aorta from 5/6 NX rats
Aortic tissue samples were dried at 90°C for 4 h and weighed. Samples were incinerated to ash at 900°C for 8 h using an electric muffle furnace (type F62700, Barnstead International, Dubuque, IA, USA), and then dissolved in 6 N HCl with Lanthanum chloride (0.1%). The solutions were diluted with distilled water, and calcium and phosphorus concentrations were measured using an Abbott Aeroset.

Data analysis
Mean ± SEM are presented for each group. One-way ANOVA followed by Dunnett's post hoc test was used to determine differences between SHAM-, vehicle- and VDRA-treated groups. *P < 0.05 versus own group Day 0, {dagger}P < 0.05 versus SHAM corresponding day and #P < 0.05 versus 5/6 NX corresponding day.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
As shown in Figure 1, serum creatinine and BUN levels were significantly and uniformly elevated in all 5/6 NX rats compared to SHAM rats on Day 0, thus confirming experimental uraemia. Treatment with paricalcitol or doxercalciferol at 0.083, 0.167 or 0.333 µg/kg for 6 weeks had no effect on serum creatinine or blood urea nitrogen as the magnitude of change was not different between vehicle- and VDRA-treated rats.


Figure 1
View larger version (29K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Serum (A) creatinine and (B) BUN levels in 5/6 NX rats fed with a high phosphorus diet (n = 6–10 per group). Rats were dosed with vehicle, paricalcitol or doxercalciferol (0.083, 0.167 and 0.333 µg/kg) i.p. three times per week for 6 weeks. On Days 0, 13 and 41, blood was drawn 24 h post-dose for serum creatinine and BUN determinations. Mean ± SEM are presented for each group. *P < 0.05 versus own group Day 0, {dagger}P < 0.05 versus SHAM corresponding day and #P < 0.05 versus 5/6 NX corresponding day.

 
Treatment with paricalcitol or doxercalciferol at 0.083 µg/kg for 6 weeks blocked PTH from rising as observed in 5/6 NX vehicle-treated rats (Figure 2), and treatment with each VDRA at 0.167 or 0.333 µg/kg consistently lowered serum PTH to the SHAM level at Weeks 2 and 6 compared to Day 0. All doses of paricalcitol increased serum calcium at Week 6, but not at Week 2, compared to Day 0. By contrast, treatment with doxercalciferol at 0.167 and 0.333 µg/kg increased serum total calcium at both Weeks 2 and 6 compared to Day 0. Treatment with paricalcitol at 0.333 µg/kg increased serum phosphorus at Weeks 2 and 6 compared to Day 0; however, these changes were not different from those observed in the 5/6 NX vehicle-treated group. By contrast, treatment with each dose of doxercalciferol increased serum phosphorus at Week 6 to levels above those observed in the 5/6 NX vehicle-treated group. Examination of the Ca x P product shows that there were no differences in Ca x P at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. By contrast, treatment with doxercalciferol at 0.167 and 0.333 µg/kg increased Ca x P at Weeks 2 and 6 above those observed in the 5/6 NX vehicle-treated group.


Figure 2
View larger version (53K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Effects of vehicle, paricalcitol or doxercalciferol (0.083, 0.167 and 0.333 µg/kg) i.p. three times per week for 6 weeks on (A) PTH, (B) total calcium, (C) phosphorus and (D) Ca x P levels in 5/6 NX rats fed with a high phosphorus diet (n = 6–10 per group). On Days 0, 13 and 41, blood was drawn 24 h post-dose for the measurement of serum creatinine and BUN. *P < 0.05 versus own group Day 0, {dagger}P < 0.05 versus SHAM corresponding day and #P < 0.05 versus 5/6 NX corresponding day.

 
As shown in Figure 3, there were no differences in aortic calcium and phosphorus contents at the end of 6 weeks among SHAM-, 5/6 NX- and paricalcitol-treated rats. However, treatment with doxercalciferol (0.167 and 0.333 µg/kg) caused a significant elevation in aortic calcium and phosphorus contents.


Figure 3
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Calcium (A) and phosphorus (B) content in the aortas from 5/6 NX rats fed with a high phosphorus diet and dosed with paricalcitol or doxercalciferol (0.083, 0.167 and 0.333 µg/kg) i.p. three times per week for 6 weeks (n = 6–10 per group). *P < 0.05 versus own group Day 0, {dagger}P < 0.05 versus SHAM corresponding day and #P < 0.05 versus 5/6 NX corresponding day.

 
Paricalcitol (0.083 µg/kg) increased aortic PWV at Week 6; however, this change was not different from the 5/6 NX vehicle-treated group at Week 6. Additionally, paricalcitol, at the two highest doses tested (0.167 and 0.333 µg/kg), had no effect on PWV. Doxercalciferol, at the lowest dose tested (0.083 µg/kg), had no effect on PWV. However, doxercalciferol, at the two highest doses tested (0.167 and 0.333 µg/kg), increased PWV at Week 6 (Figure 4).


Figure 4
View larger version (28K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Effects of vehicle, paricalcitol or doxercalciferol (0.083, 0.167 and 0.333 µg/kg) i.p. three times per week for 6 weeks on PWV in 5/6 NX rats fed with a high phosphorus diet (n = 6–10 per group). PWV increased at Week 6 by treatment with doxercalciferol (0.167 and 0.333 mg/kg). PWV increased modestly at Week 6 by treatment with paricalcitol (0.083 mg/ kg); however, this increase was most likely an artifact, as PWV did not increase with the two higher doses of paricalcitol tested. *P < 0.05 versus own group Day 0, {dagger}P < 0.05 versus SHAM corresponding day and #P < 0.05 versus 5/6 NX corresponding day.

 
Echocardiographic analysis of the myocardium in 5/6 NX rats treated with each dose of paricalcitol revealed no echogenic areas. Echocardiographic analysis of the myocardium revealed no echogenic areas at the lowest dose of doxercalciferol. However, in 9 out of 10 rats treated with doxercalciferol at 0.167 µg/kg, echocardiographic analysis of the myocardium revealed the presence of echogenic areas throughout the left ventricular walls, aorta and aortic valves, suggestive of calcification (Figure 5). Similar results were observed in rats treated with the highest dose of doxercalciferol (0.333 µg/kg).


Figure 5
View larger version (64K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 5 Representative parasternal long axis views of left ventricles from 5/6 NX rats fed with a high phosphorus diet and dosed i.p. three times per week for 6 weeks with (A) paricalcitol (0.333 µg/kg) or (B) doxercalciferol (0.167 µg/kg) (n = 6–10 per group). No calcification was produced by paricalcitol, while marked cardiac/aortic calcification occurred in 9 out of 10 rats treated with doxercalciferol. LV—left ventricle and Ao—aorta.

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
In stage 5 CKD, cardiovascular complications are the most frequent cause of morbidity and mortality [1,2]. Vascular calcification is associated with the increased mortality of these patients’ population and has become an important area of research over the past decade [3]. The mechanism for vascular calcification is complex and not well understood. It has been postulated that loss of calcification inhibition, induction of bone formation, circulating nucleational complexes from bone and cell death may predispose the vasculature to calcification [4]. In addition, changes in calcium and phosphorus balance, which are typical in stage 5 CKD, may have direct effects on smooth muscle cells that promote bone-like differentiation [4]. Calcitriol, VDRAs such as paricalcitol (19-nor-1{alpha},25(OH)2D2) and doxercalciferol (1{alpha}(OH)D2) and calcimimetics are currently used to manage SHPT and renal osteodystrophy. However, in stage 5 CKD patients with hyperphosphataemia and hypercalcaemia, some VDRAs may exacerbate vascular calcification as a result of further increases in serum calcium and phosphorus levels. Although the perception about vascular calcification induced by VDRAs may be well founded, there are no clear data to support that treatment with calcitriol and VDRAs directly contributes to vascular calcification [16]. Additionally, there is no clear evidence in dialysis patients that VDRA administration is directly responsible for the induction of vascular calcification [17]. The purpose of this study was to determine if paricalcitol and doxercalciferol have differential effects on aortic calcification and compliance in the 5/6 NX rats fed with a high phosphorus diet. In this study, we demonstrate marked differential effects of two different VDRAs, as treatment with doxercalciferol (0.167 and 0.333 mg/kg) for 6 weeks resulted in aortic calcification and increases in PWV, effects not observed in paricalcitol-treated animals.

Our findings on PTH, Ca and P from the 5/6 NX rats treated with paricalcitol and doxercalciferol (0.167 and 0.333 µg/kg) for 6 weeks are consistent with a previous report by Slatopolsky et al. [16] that doxercalciferol is more stimulatory than paricalcitol regarding the increase in serum Ca, P and Ca x P. Unlike paricalcitol, doxercalciferol is a pro-hormone and requires an activation step in the liver to produce the active VDRA. Paricalcitol is slightly less potent than doxercalciferol (0.6:1) in suppressing serum PTH, but is 5- to 10-fold less calcaemic and phosphataemic [16]. For purposes of this study, dose comparisons should be performed accordingly, as pharmacokinetic analysis of VDRA levels was not determined. The doses for this study were strictly chosen on the basis of PTH suppression in this model of animal model of CKD.

In this study, we have demonstrated that paricalcitol has no significant risk of inducing vascular calcification compared to the use of doxercalciferol at doses producing comparable PTH suppression. While not observed with the lowest dose of doxercalciferol, increases in PWV, an index of aortic compliance, and aortic calcium and phosphorus contents were observed in 5/6 NX rats treated with doxercalciferol (0.167 and 0.333 µg/kg) for 6 weeks. Finally, while not observed with the lowest dose of doxercalciferol, echocardiographic analysis revealed marked echogenic areas within the wall of the left ventricle, aortic valve and aortic arch in 9 out of 10 5/6 NX rats treated with doxercalciferol (0.167 µg/kg) for 6 weeks. Similar results were observed in rats treated with the highest dose of doxercalciferol (0.333 µg/kg). By contrast, none of these effects were observed in 5/6 NX rats treated with paricalcitol.

To determine whether differences in aortic calcification and PWV were due to the differential effects of paricalcitol and doxercalciferol on serum calcium, phosphorus and Ca x P, we purposely tested these VDRAs at a dose used to induce hypercalcaemia in rats with established SHPT (0.667 µg/kg; i.p.; three times per week for 2 weeks). As anticipated, both paricalcitol and doxercalciferol effectively suppressed PTH and caused similar increases in serum total calcium and phosphorus and Ca x P compared to SHAM and 5/6 NX rats [18]. PWV determinations in this group of rats showed that doxercalciferol increased PWV, while paricalcitol had no effect. Supporting this is the fact that there was no difference in aortic calcium and phosphorus contents among SHAM-, 5/6 NX- and paricalcitol-treated rats, whereas treatment with doxercalciferol caused significant elevations in aortic calcium and phosphorus contents at the end of 2 weeks. Again, this observation suggests that mechanisms beyond hyperphosphataemia and hypercalcaemia may be responsible for the differential effects of paricalcitol and doxercalciferol on vascular calcification.

A review of the published literature confirms that different VDRAs exert differential effects on vascular calcification independent of serum calcium, phosphorus and Ca x P. Recently, Cardus et al. [19] demonstrated that a hypercalcaemic dose of paricalcitol (3 µg/kg) and a clinically comparable dose of calcitriol (1 µg/kg) had differential effects on vascular calcification in 5/6 NX rats. Both compounds raised serum calcium and Ca x P compared to control, but only calcitriol caused an increase in the calcification of the abdominal aorta. Similar results were observed by Hirata et al. [20] as they demonstrated that 1,25(OH)2D3 induced the calcification of the aorta in 5/6 NX rats, while 22-oxacalcitriol, a unique 1,25(OH)2D3 analogue, did not cause the calcification of the aorta. These results support the fact that different VDRAs exert differential effects on vascular calcification independent of serum calcium, phosphorus and Ca x P.

The mechanism for the differential effects of paricalcitol and doxercalciferol on aortic calcification in vivo remains unclear as no aortic calcification was observed in 5/6 NX rats treated with paricalcitol (0.667 µg/kg), despite hypercalcaemia and hyperphosphataemia in both treatment groups. From various human and mouse genetic studies, a deficiency of tissue-derived and circulating mineralization inhibitors such as pyrophosphate [21], matrix gla protein [5] and fetuin [22] may lead to vascular calcification. Recent evidence suggests that bone proteins such as osteopontin [23] and osteocalcin [24] and bone formation in carotid plaques [25] supports the hypothesis that osteogenic mechanisms may also play a role in vascular calcification. It has also been proposed that VDRAs may exert their differential effects by regulating various steps in VDR function including: binding differently to the nuclear vitamin D receptor (VDR), interacting with different vitamin D response elements (VDREs) and VDR homo- or heterodimerization with the retinoid X receptor [26]. Additionally, selective recruitment of transcriptional coactivators such as SRC-1, GRIP1 and RAC3 to target genes may act to remodel chromatin or act directly on the transcriptional apparatus [27–29]. Vascular calcification is likely an active process regulated by different, yet interacting mechanisms involving not only the vasculature, but also other organs such as bones and liver. Therefore, it is conceivable that VDRAs modulate calcification genes in different tissues differentially, leading to differential protective effects on vascular calcification in vivo.

In conclusion, we demonstrate that paricalcitol and doxercalciferol display differential effects on aortic calcification in vivo, which is independent of serum Ca, P and Ca x P, suggesting a different mechanism of action between these two VDRAs.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Weiner DE, Tighiouartc H, Amin MG, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol (2004) 15:1307–1315.[Abstract/Free Full Text]
  2. Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol (2006) 17:2034–2047.[Abstract/Free Full Text]
  3. London GM, Marchais SJ, Guerin AP, et al. Arteriosclerosis, vascular calcifications and cardiovascular disease in uraemia. Curr Opin Nephrol Hypertens (2005) 14:525–531.[Web of Science][Medline]
  4. Giachelli CM. Vascular calcification mechanisms. J Am Soc Nephrol (2004) 15:2959–2964.[Abstract/Free Full Text]
  5. Mackey RH, Venkitachalam L, Sutton-Tyrrell K. Calcifications, arterial stiffness and atherosclerosis. Adv Cardiol (2007) 44:234–244.[Web of Science][Medline]
  6. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med (2000) 342:1478–1483.[Abstract/Free Full Text]
  7. Oh J, Wunsch R, Turzer M, et al. Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation (2002) 106:100–105.[Abstract/Free Full Text]
  8. Lehto S, Niskanen L, Suhonen M, et al. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol (1996) 16:978–983.[Abstract/Free Full Text]
  9. Davies MR, Hruska KA. Pathophysiological mechanisms of vascular calcification in end-stage renal disease. Kidney Int (2001) 60:472– 479.[CrossRef][Web of Science][Medline]
  10. Brown AJ, Dusso AS, Slatopolsky E. Vitamin D analogues for secondary hyperparathyroidism. Nephrol Dial Transplant (2002) 17(Suppl_10):10–19.[Abstract]
  11. Martin KJ, Gonzalez EA. Vitamin D analogs: actions and role in the treatment of secondary hyperparathyroidism. Semin Nephrol (2004) 24:456–459.[Web of Science][Medline]
  12. Teng M, Wolf M, Lowrie E, et al. Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med (2003) 349:446–456.[Abstract/Free Full Text]
  13. Teng M, Wolf M, Ofsthun MN, et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol (2005) 16:1115–1125.[Abstract/Free Full Text]
  14. Tentori F, Hunt WC, Stidley CA, et al. Mortality risk among hemodialysis patients receiving different vitamin D analogs. Kidney Int (2006) 70:1858–1865.[CrossRef][Web of Science][Medline]
  15. Slatopolsky E, Finch J, Ritter C, et al. A new analog of calcitriol, 19-nor-1,25-(OH)2D2, suppresses parathyroid hormone secretion in uraemic rats in the absence of hypercalcaemia. Am J Kidney Dis (1995) 26:852–860.[Web of Science][Medline]
  16. Mizobuchi M, Finch JL, Martin DR, et al. Differential effects of vitamin D receptor activators on vascular calcification in uraemic rats. Kidney Int (2007) 72:709–715.[CrossRef][Web of Science][Medline]
  17. Wolisi GO, Moe SM. The role of vitamin D in vascular calcification in chronic kidney disease. Semin Dial (2005) 18:307–314.[CrossRef][Web of Science][Medline]
  18. Wu-Wong JR, Noonan W, Ma J, et al. Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther (2006) 318:90–98.[Abstract/Free Full Text]
  19. Cardus A, Panizo S, Parisi E, et al. Differential effects of vitamin D analogs on vascular calcification. J Bone Miner Res (2007) 22:860–866.[CrossRef][Web of Science][Medline]
  20. Hirata M, Katsumata K, Endo K, et al. In subtotally nephrectomized rats 22-oxacalcitriol suppresses parathyroid hormone with less risk of cardiovascular calcification or deterioration of residual renal function than 1,25(OH)2 vitamin D3. Nephrol Dial Transplant (2003) 18:1770–1776.[Abstract/Free Full Text]
  21. Rutsch F, Ruf N, Vaingankar S, et al. Mutations in ENPP1 are associated with ‘idiopathic’ infantile arterial calcification. Nat Genet (2003) 34:379–381.[CrossRef][Web of Science][Medline]
  22. Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet (2003) 361:827–833.[CrossRef][Web of Science][Medline]
  23. Giachelli CM, Bae N, Almeida M, et al. Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques. J Clin Invest (1993) 92:1686–1696.[Web of Science][Medline]
  24. Levy RJ, Schoen FJ, Levy JT, et al. Biologic determinants of dystrophic calcification and osteocalcin deposition in glutaraldehyde-preserved porcine aortic valve leaflets implanted subcutaneously in rats. Am J Pathol (1983) 113:143–155.[Abstract]
  25. Hunt JL, Fairman R, Mitchell ME, et al. Bone formation in carotid plaques: a clinicopathological study. Stroke (2002) 33:1214–1219.[Abstract/Free Full Text]
  26. Issa LL, Leong GM, Sutherland RL, et al. Vitamin D analogue-specific recruitment of vitamin D receptor coactivators. J Bone Miner Res (2002) 17:879–890.[CrossRef][Web of Science][Medline]
  27. Onate SA, Tsai SY, Tsai MJ, et al. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science (1995) 270:1354–1357.[Abstract/Free Full Text]
  28. Hong H, Kohli K, Trivedi A, et al. GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA (1996) 93:4948–4952.[Abstract/Free Full Text]
  29. Li H, Gomes PJ, Chen JD. RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci USA (1997) 94:8479–8484.[Abstract/Free Full Text]
Received for publication: 10. 8.07
Accepted in revised form: 11. 6.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/12/3824    most recent
gfn375v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Noonan, W.
Right arrow Articles by Reinhart, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Noonan, W.
Right arrow Articles by Reinhart, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?