Paricalcitol is the third generation of vitamin D analog, and is a selective activator of VDR used for the treatment of secondary hyperparathyroidism.44
Compared with calcitriol, paricalcitol reduces PTH, with significantly fewer episodes of hypercalcemia in hemodialysis patients.45
Reduced episodes of hypercalcemia among patients who received paricalcitol compared to calcitriol could be explained due to reduced stimulation of intestinal calcium transport proteins.46
Calcitriol in uremic rats fed with a high-phosphorus diet enhances intestinal calcium absorption, because calcitriol promotes calbindin expression, whereas paricalcitol does not.47
There are also data on lower absorption rates of calcium and phosphorus among patients receiving paricalcitol, compared with calcitriol.48
The vascular calcification process in chronic kidney disease is also directly influenced by paricalcitol. Activation of VDR has been shown to decrease the process of vascular calcification, the main cardiovascular feature of chronic kidney disease, through suppression of calcification inducers such as type I collagen, bone sialoprotein, interleukin-1β, and tumor necrosis factor-alpha, or through activation of calcification supressors: matrix Gla protein, osteopontin, and osteocalcin.50
Li et al51
demonstrated direct protection from vascular calcifications with paricalcitol, and found that paricalcitol could influence proteins involved in the smooth muscle cell calcification process, including bone morphogenetic protein-2 (BMP2), tumor necrosis factor-alpha, and osteopontin. Osteopontin could directly regulate vascular calcification and was found to contribute to the inhibitory actions of paricalcitol in the calcification of smooth muscle cell. The direct influence of paricalcitol on VDRs located on vascular smooth muscle cells could be explained by different effects of paricalcitol on target genes involved in the pathogenesis of vascular calcifications, independently of previously suggested mechanisms, such as modulation of the inflammatory response or different hyperphosphathemic and hypercalcemic effects.
Paricalcitol seems to have several mechanisms of action, because activation of the VDR intervenes in pathways associated with cardiovascular disease (suppression of renin transcription, antiproliferative effects, antifibrotic effects).52
Data support a potential role of selective VDR activation in preventing the pathogenesis of atherosclerosis in chronic kidney disease. Activation of VDR also impacts the cardiovascular system by decreasing the activation of the renin-angiotensin-aldosterone system. There is evidence of an inverse relationship between vitamin D levels and plasma renin activity.53
Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in a rat model of chronic renal failure.54
In a rat model of gentamicin-induced renal injury, paricalcitol prevented upregulated inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, interferon-gamma), nuclear factor-kappaB and phosphorylated ERK1/2 expression, and adhesion molecules (monocyte chemoattractant protein-1, ICAM-1, VCAM-1), and they reversed the transforming growth factor (TGF)-beta1-induced epithelial-to-mesenchymal transition process and extracellular matrix accumulation.55
Paricalcitol has significant immunomodulatory activity via VDR agonism, based on its inhibition of dendritic cells, which are important in the pathogenesis of atherosclerosis.56
The antioxidative properties of paricalcitol were demonstrated, in an animal model of contrast-induced nephropathy, by lower levels of serum malondialdehyde and kidney thiobarbituric acid-reacting substances in the paricalcitol group.57
Antifibrotic effects of paricalcitol were reported by Meems et al58
in an animal model: paricalcitol reduced myocardial fibrosis and preserved diastolic left-ventricular function due to pressure overload associated with reduced fibrosis. A similar study revealed the protective effect of enalapril and paricalcitol, alone or in combination, on cardiac oxidative stress in uremic rats.59
Paricalcitol prevented cisplatin-induced kidney injury by suppressing fibrotic, apoptotic, and proliferative factors in an animal model; paricalcitol suppressed expression of TGF-β1, Smad signaling, mitogen-activated protein kinase signaling, p53-induced apoptosis, and p27(kip1).60
Additionally, combination of enalapril and paricalcitol reduced glomerulosclerosis, proteinuria, and inflammation – when measured as monocyte chemoattractant protein-1 (MCP-1) in uremic rats – via suppression of TGFβ-1 and Smad2.61
Paricalcitol combined with enalapril had an additional protective effect on aortic inflammatory and oxidative injury biochemical markers in atherosclerotic mice.62
Kong et al63
tested, in an interesting study of spontaneously hypertensive rats, the effects of losartan, paricalcitol, doxercalciferol, a combination of losartan and paricalcitol, or a combination of losartan and doxercalciferol, on the development of left-ventricular hypertrophy. Echocardiograpy demonstrated a 65% to 80% reduction in left-ventricular wall thickness with losartan, paricalcitol, or doxercalciferol monotherapy, and almost complete prevention of left-ventricular hypertrophy with the combination therapies. Renal and cardiac renin expression was markedly increased in losartan-treated animals, but nearly normalized with combination therapy. These data demonstrate that vitamin D analogs have potent antihypertrophic activity, partly by suppressing renin in the kidney and heart. Paricalcitol also suppresses the progression of left-ventricular hypertrophy, myocardial and perivascular fibrosis, and myocardial arterial vessel thickness in uremic rats by upregulating the VDRs.64
Fraga et al65
demonstrated that paricalcitol prevented decrease in myocardial VDR expression. As VDRs are expressed in cardiac myocytes, the effect of paricalcitol could have a clinical impact on uremic cardiomyopathy, a common complication in patients with chronic kidney disease, characterized by cardiac fibrosis, cardiac hypertrophy, and diastolic dysfunction. Wu-Wong et al66
demonstrated that VDR activation with paricalcitol improved endothelial function, measured as endothelial-dependent vasorelaxation in a chronic kidney disease rat model, independently of the parathyroid hormone suppression effect.
As vascular calcification is associated with cardiovascular disease in chronic kidney patients, there is concern over vitamin D’s possible effects on calcium, phosphorus, and consequently, on vascular calcifications. Mizobuchi et al67
demonstrated that paricalcitol, in contrast to calcitriol and doxercalciferol, had no effect on the serum calcium-phosphate product or aortic calcium content in uremic rats. A higher dose of paricalcitol still had no effect, but lowering doxercalciferol levels did not increase the calcium-phosphate product; rather, it increased the aortic calcium content, suggesting independent paricalcitol-mediated mechanisms for protection from vascular calcification. Cardús et al68
tested the effects of calcitriol and paricalcitol on vascular smooth muscle-cell calcification in an animal end-stage renal disease model, and concluded that calcitriol, but not paricalcitol, increased calcification of vascular smooth muscle cells, independently of the levels of calcium and phosphate.
Besides these experimental data, observational studies in hemodialysis patients reported improved cardiovascular and all-cause survival among those receiving selective VDR activation therapies. The selective VDR activation agent paricalcitol has been associated with greater survival than nonselective VDR activators such as calcitriol. Indeed, one observational study demonstrated a better 36-month survival rate of patients on dialysis treated with paricalcitol, compared with calcitriol.69
A possible explanation for the differential effects of paricalcitol and calcitriol on survival is mineral metabolism. Calcitriol could have a larger gastrointestinal absorption rate of calcium and phosphorus than does paricalcitol, so vascular calcification and death from cardiovascular causes could be increased in patients receiving calcitriol. Another observational study among 7731 hemodialysis patients also demonstrated better survival in patients on doxercalciferol and paricalcitol, versus calcitriol.70
A recent observational study71
also revealed that paricalcitol was associated with improved 2-year survival in dialysis patients, even with low serum iPTH levels, so the differential effects of paricalcitol and calcitriol on survival are not correlated only with different effects on mineral metabolism or on PTH; they could be related to additional pleiotropic effects of paricalcitol.