The Role of Paricalcitol in Chronic Kidney Disease
Elevations in serum phosphate (p=0.025) and calcium x phosphate product (p=0.061) were less common in haemodialysis patients receiving paricalcitol compared with doxercalciferol, despite a comparable suppression of PTH levels observed in the two treatment groups.51
following a switch from calcitriol to paricalcitol was accompanied by a significant reduction in serum calcium (p=0.0003) and serum phosphate levels (p=0.027).44
Clinical support for the reduced intestinal calcium absorption observed in animal models was provided by results from a single-centre, double-blind, randomised, crossover trial by Lund et al.,52 who found that intestinal absorption of calcium was approximately 14 % less in paricalcitol-treated patients compared with calcitriol-treated patients.52
Figure 2: Aortic Calcium Content in Nephrectomised Rats Following Treatment with Vitamin D Receptor Activators
mg/g of wet weight tissue
In addition, treatment of dialysis patients with oral paricalcitol leads to significant decreases in bone activity markers (bone-specific alkaline phosphatase, osteocalcin, collagen C-telopeptides: p<0.001; tartrate-resistant acid phosphatase isoform 5b: p=0.006) relative to placebo, demonstrating a clear trend towards normalisation of the high-turnover bone disease associated with SHPT.41
The main cardiovascular effects associated with vitamin D deficiency include hypertension, vascular calcification, myocardial and arterial thickening with arterial stiffness and left ventricular hypertrophy (LVH). Importantly, there is growing evidence that administration of VDR activators has a beneficial effect on cardiovascular disease that may, in part, explain the increased survival observed in patients receiving these drugs.11,22
Paricalcitol and the Cardiovascular System Several studies suggest that different consequences of vitamin D deficiency and reduced VDR activation are associated with vascular calcification, vascular dysfunction, and all-cause and cardiovascular mortality, both in the general population9,53 CKD.7,8,54,55
and in patients with
The effect of VDR activators on VC are thought to be direct, for example, via VDR-mediated effects at vascular smooth muscle cells,67
hyperphosphataemia.21,66
and indirect, mediated through hypercalcaemia and These two different mechanisms may help
Emerging data have
linked paricalcitol treatment with reduced vascular calcification,56 improved heart function57
and reduction of myocardial fibrosis.58 Vascular Calcification
Vascular calcification (VC) is frequently observed in patients with CKD and is closely associated with cardiovascular morbidity and mortality.59 VC is largely restricted to the arteries and occurs in two locations, the intima and the media. Intimal calcification is part of the atherosclerotic process and can occur in any person with atherosclerosis whether or not they have CKD. Medial layer calcification is more common in patients with CKD.60
The morbidity associated with
VC is presumed to result from increased vascular stiffness with reduced vessel elasticity or compliance.61
The pathophysiology of VC is not
completely understood but it is clear that it is a multifactorial and active process involving altered mineral metabolism, as well as changes in systemic and local factors that can promote or inhibit VC.25,62,63
The
association between the use of VDR activators and VC merits a specific comment. The use of high dose of VDR activators has been associated in preclinical and clinical studies with increments in VC. However, several subsequent studies have shown an inverse relationship between different serum VDR activator levels and VC.10,54,64,65
This
apparent discrepancy can be explained by a concentration-dependent effect of VDR activators. Normal serum levels of 25-D and 1,25-D have been consistently associated with less VC, better vascular function and improved outcomes whereas high concentrations of VDR activators have been shown to stimulate VC, an effect that seems to be at least partly reversible with the cessation of treatment.66
EUROPEAN NEPHROLOGY
to explain the dose-dependent effects of VDR activators. The newer VDR activators have been shown to induce less VC compared with older agents, likely due to a more selective action at the VDR and/or because of their lower hypercalcaemic or hyperphosphataemic action. The notion that selective VDR activators result in less VC has been supported by data from experimental models. Clinically relevant dosages of calcitriol and paricalcitol were found to protect against aortic calcification in a mouse model of CKD,68
but at higher
doses calcitriol, but not paricalcitol, increased vascular smooth muscle cell calcification in nephrectomised rats.56
This effect was
independent of serum calcium and phosphate levels and the decreases in serum PTH levels were similar for both treatments. The same study also showed that treatment with hypercalcaemic doses of calcitriol caused higher pulse pressure, likely due to the extensive calcification observed in arteries. Neither increased arterial calcification nor a higher pulse pressure were noted in the paricalcitol-treated rats.56
In two other experimental studies, paricalcitol treatment also resulted in less VC compared with other VDR activators (see Figure 2). The effect appeared to be independent of calcium, phosphate or calcium x phosphate product levels, suggesting a different mechanism of action of these two VDR activators.69, 70
One of these studies explored this further
and found that doxercalciferol treatment increased the mRNA and protein expression of the bone-forming-related markers such as Runx2 and osteocalcin in the aorta, whereas paricalcitol did not.69
These
observations in animal models require further experimental and human evaluation to clarify the likely molecular and genetic background and mechanisms by which VDR activators may mediate their differential effects on the process of VC.36
85
10 15 20 25 30 35 40 45
0 5
NC UC Ca = calcium; NC = normal rats; UC = vehicle.
Uraemic rats were treated with vehicle, calcitriol (1,25D3), doxercalciferol (1aD2) or paricalcitol (19-nor). Values are mean ±SEM; p<0.0001 by analysis of variance.
**p<0.01 versus UC ##
p<0.01 versus paricalcitol. Reproduced with permission from Mizobuchi et al., 2007.69 1,25D3 1αD2 19-nor
## **
## **
Aortic Ca content
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