Abstract

Vitamin D has been recently associated with several renal, cardiovascular and inflammatory diseases, beyond mineral metabolism and bone health. This is due in part to widespread expression of vitamin D receptor (VDR) on tissues and cells such as heart, kidney, immune cells, brain and muscle. In chronic kidney disease (CKD) and other chronic disorders, vitamin D deficiency [serum 25(OH)D <20 ng/mL] is very common and is associated with adverse outcomes. Paricalcitol, a selective activator of VDR, has demonstrated in several experimental and clinical studies of diabetic and non-diabetic CKD a favourable profile compared to other VDR activators, alone or as add-on to standard therapy. These beneficial effects are mediated by different actions such as reduction of oxidative stress, inflammation, downregulation of cardiac and renal renin expression, downregulation of calcifying genes and direct vascular protective effects. Furthermore, paricalcitol beneficial effects may be independent of baseline serum parathyroid hormone (PTH), calcium and phosphate levels. These benefits should be confirmed in large and well-designed ongoing clinical trials.

Vitamin D in chronic kidney disease patients

Vitamin D is essential not only in mineral metabolism homeostasis, but also to human health. Several epidemiological studies have shown an important association between vitamin D deficiency and cardiovascular mortality, hypertension, neoplasms and immunity disorders. The nuclear vitamin D receptor (VDR) is present in many human tissues. VDR is most highly expressed in small intestine, colon, kidney, bone and skin, but also in other tissues and cell types like the vascular system, endocrine organs, immune system, brain and muscle [1]. Vitamin D has numerous non-calcemic functions [2]. Around 80% of vitamin D functions are autocrine/paracrine effects independent of endocrine control of mineral metabolism. The remaining 20% are endocrine functions, such as actions on the intestine, bone and parathyroid glands. One of the most important autocrine effects of VDR activation is on the cardiovascular system and has been associated with reduced cardiovascular risk. Chronic kidney disease (CKD) patients have high rates of cardiovascular mortality, probably in part due to this vitamin D deficiency. Furthermore, several studies have suggested that therapy of vitamin D deficiency reduces this high mortality. However, an excessive treatment could also increase the cardiovascular risk [3].

The vitamin D status in CKD patients is assessed by measuring 25-hydroxy-vitamin D [25(OH)D] levels in blood. The values between 20 and 30 ng/mL are considered insufficient, and <20 ng/mL, deficient [4]. There is a high prevalence of vitamin D deficiency in healthy and ill population [4].Vitamin D deficiency and insufficiency are also very common in CKD patients, especially in winter [5]. Other causes contributing to vitamin D deficiency include lower intake of vitamin D, especially vegetables, less sun exposure and upregulated 25(OH)D-24-hydroxylase [6]. In CKD, vitamin D supplementation needs active VDR activators (calcitriol or paricalcitol). However, correction of abnormal uptake of 25(OH)D by monocyte 1-hydroxylase and increased renal 25(OH)D uptake by megalin are also desirable. Calcidiol, calcitriol or paricalcitol can upregulate 25(OH)D-24-hydroxylase, thereby limiting local calcitriol production for autocrine/paracrine VDR activation [7]. Low levels of serum vitamin D have been associated with increased cardiovascular risk, hypertension and mortality in haemodialysis patients [8–11].

Correction of vitamin D deficiency

Clinical and animal studies support the existence of biphasic cardiovascular effects of vitamin D, in which lower doses suppress and higher doses increase the cardiovascular risk [8]. The therapeutic window is probably narrower than suggested, as an altered vitamin D metabolism in CKD patients sensitizes them to toxicity [12, 13]. Replacement with ergocalciferol or 25-OH-vitamin D increases 25(OH)D levels in most, but not all patients [14]. The reasons for this variability are not well known, but differential 25-hydroxyvitamin D-24-hydroxylase activity and FGF-23 may contribute [15].

A meta-analysis of prospective randomized clinical trials from 1996 to 2009 suggested that vitamin D supplementation at moderate to high doses may reduce the cardiovascular disease risk [16]. A nutritional trial currently is randomizing 20 000 healthy older men and women throughout the USA to receive either 2000 IU of vitamin D3 (cholecalciferol) per day or placebo for 5 years for primary prevention of heart disease, stroke and cancer. The treatment with an active VDR activator overrides the increase in mortality associated with a deficit of 25(OH) vitamin D [17].

VDR activation in CKD: the role of paricalcitol

There are different treatments to activate the VDR. Calcitriol is the endogenous active molecule. Other molecules need to be activated in kidney, liver or both to be transformed into calcitriol as vitamin D2 or ergocaciferol, 1-hydroxy-vitamin D2 (doxercalciferol), vitamin D3 (cholecalciferol), [25(OH)D3] (calcidiol) and 1-hydroxy-vitamin D3 (alfacalcidol). Other active molecules that do not require VDR transformation to activate the VDR, called selective activators, are paricalcitol (19-nor-1,25-dihydroxy-vitamin D2) and maxacalcitol (22-oxacalcitriol). There are clinical recommendations on treatment with nutritional vitamin D in the general population or patients with CKD. The Institute of Medicine recommended target 25(OH)D levels >20 ng/mL [18]. The recommended daily intake under 70 years is 600 IU/day of vitamin D2 or D3, while over 70 should be 800 IU/day. The KDIGO 2009 guidelines recommend to measure and treat vitamin D insufficiency in patients with CKD stages 3–5, but there are no recommendations on vitamin D by cardiological societies, although an expert panel recommended to assess vitamin D status and to treat vitamin D deficiency in all patients at high cardiovascular risk.

Active vitamin D is necessary for 25(OH)D internalization and activation. For this reason, the exclusive treatment with 25(OH)D may not be sufficient to activate the VDR in the absence of endogenous calcitriol [7]. In CKD, there are guidelines on the use of active vitamin D for the treatment of secondary hyperparathyroidism, but little guidance outside this specific situation. The selection of an active molecule and the dose to be used are debated, but many observational studies have shown that paricalcitol has a better protective effect on cardiovascular risk than calcitriol [19]. There are doubts about the indication of these molecules in patients with PTH <150 ng/mL. A particular worry in these patients is the risk of developing adynamic bone and increased vascular calcification. The following paragraphs discuss the beneficial effects of paricalcitol versus calcitriol on the cardiovascular system, even in patients with low PTH.

Survival

In observational studies, VDR activators were associated with improved survival and the effects were more marked for paricalcitol [19–25]. The increased mortality of CKD patients with serum 25(OH)D <30 ng/mL is not observed in patients treated with calcitriol or paricalcitol [24]. The improved survival in patients treated with paricalcitol has been observed at any PTH level, including patients with very high PTH [25]. For several decades, VDR activators have been used to treat secondary hyperparathyroidism (PTH levels >300 pg/dL). In addition, decreased mortality has also been observed in paricalcitol-treated CKD patients with PTH <150 ng/mL [26].

Vascular effects and the heart

Experimental studies have shown that paricalcitol, but not calcitriol, protects from vascular calcifications in uremic rats [27, 28]. Paricalcitol reduces the expression of genes involved in atherosclerosis: vascular cell growth, thrombus formation, fibrinolysis and endothelial regeneration-related genes [29]. Paricalcitol also mitigates disturbed aortic gene expression induced by uremia [30].

In rats, paricalcitol prevents the progression of left ventricular hypertrophy (LVH) and the development of heart failure [31–34]. It also decreases heart renin expression [33]. The combination of losartan and paricalcitol is able to maintain cardiac renin levels, which rise on monotherapy with losartan, adding effects in reducing LVH. Paricalcitol also decreases LVH and fibrosis secondary to uremia [34].

Despite these encouraging preclinical data, in the PRIMO randomized placebo-controlled trial, paricalcitol failed to reduce LVH in CKD patients with moderate LVH and iPTH 150–300 pg/ml [35]. Reduction in LVH was the primary endpoint of the study. Paricalcitol reduced BNP levels, left auricular volume and hospitalization for cardiovascular reasons. Most patients were treated with renin–angiotensin–aldosterone system (RAAS) inhibitors.

Potential renoprotective effects of vitamin D receptor activation

Paricalcitol has demonstrated potential renoprotective effects in experimental animals [33, 42–44]. It reduced fibrosis following unilateral ureteral obstruction [36], decreased proteinuria as add-on to RAAS blockers in diabetic nephropathy [37] and was nephroprotective in models of cyclosporine toxicity [38].

An antiproteinuric effect of paricalcitol has been described in human CKD, especially in diabetic kidney disease [39]. However, the largest trial to date, the VITAL trial, missed significance in its primary endpoint [39] and the results were confused by widespread vitamin D insufficiency among participants [40]. Clearly, we need better designed clinical trials to determine the true role of paricalcitol and other VDR activators in these conditions. An ongoing Spanish multi-center, open-label, randomized clinical trial (the PALIFE study) [41] will randomize 236 patients with diabetic and non-diabetic CKD to paricalcitol plus standard care or standard care only, to assess the effect on albuminuria, systemic and renal inflammation, renal fibrosis and endothelial function, among others. Importantly, this study will only recruit patients with serum 25(OH)D levels >20 ng/mL. Endpoints will be analysed at 6 months (end of treatment period) and after 2 months of wash-out (total follow-up 8 months). A recent meta-analysis of nine studies comparing paricalcitol with placebo concluded that paricalcitol suppressed serum iPTH and reduced proteinuria [42].

Potential mechanisms involved in the beneficial effects of VDR activation on CVD

Several mechanisms may contribute to the differential survival between calcitriol and paricalcitol in CKD [19]. Thus, compared with those not treated with a VDR activator, the use of paricalcitol appears to reduce mortality regardless of the dose used [25] and at any level of serum PTH [23]. Dialysis patients with PTH <150 pg/mL have increased cardiovascular risk and decreased survival, probably related to adynamic bone and vascular calcification [43]. Patients treated with paricalcitol and PTH <150 pg/mL have better survival than those treated with calcitriol or not receiving vitamin D [26]. The survival advantage in patients treated with paricalcitol was independent of calcium, phosphorus, PTH, age and albumin [26]. Specific paricalcitol effects such as reduced expression of calcifying genes, oxidative stress, inflammation, intestinal absorption of calcium and phosphorus and calcium release from bone may modulate cardiovascular biology and vascular calcification.

Reduced expression of calcifying genes

When compared with other VDR activators, paricalcitol may directly protect from vascular calcification, as demonstrated in cells and in animal models [28, 44, 45]. This protective effect would be useful even in patients with increased susceptibility to vascular calcification, such as inflammed patients and those with adynamic bone disease [28]. The different effects of VDR activators on vascular calcification cannot be totally accounted for by the differences in calcium-phosphate product and direct effects of paricalcitol on the vascular wall have been observed [46]. 1-Hydroxyvitamin D2 (doxercalciferol) or calcitriol increased Runx2 (Cbfα1) and osteocalcin mRNA expression in the aorta, independent of the calcium-phosphate product, whereas paricalcitol did not. Runx2 (Cbfα1) and osteocalcin modulate skeletal mineralization and vascular calcification [46, 47]. Runx2 promotes differentiation into an osteoblast or bone producing cell.

Reduced oxidative stress and inflammation

In animal models, paricalcitol reduces inflammation and oxidative stress and prevents plaque formation in ApoE−/− mice [48]. In haemodialysis patients, paricalcitol decreases interleukins 1(IL1), IL6 and tumor necrosis factor [49]. VDR activation reduced kidney inflammatory molecules and limited the profibrogenic and proinflammatory response of kidney cells to metabolic abnormalities including hyperglycemia [49, 50], and decreased renin activity in cardiomyocytes [32].

Reduced intestinal absorption of calcium and phosphorus

In rats, paricalcitol is slightly less potent than doxercalciferol (0.6:1) in suppressing serum PTH, but is 5- to 10-fold less calcemic and phosphatemic [45]. In haemodialysis patients, intestinal calcium absorption was 14% lower on paricalcitol than on calcitriol [51]. Paricalcitol resulted in lower levels of intestinal calbindin, a protein involved in intestinal calcium transport, than calcitriol [52]. This lower absorption of calcium may be important to prevent vascular calcification: given that CKD bone has a reduced ability to bind calcium, absorbed calcium contributes to vascular calcification even in the absence of changes in serum calcium level [43].

Decreased calcium release from bone

Release of calcium from bone is 10 times lower in rats treated with paricalcitol than with calcitriol [53]. Paricalcitol increased the bone turnover, increasing the osteoclastic activity less than calcitriol, while increasing the osteoclast activity more than calcitriol, leading to an increased bone volume, trabecular thickness and osteoid surface [54].

Conclusion

In observational studies, activation of the VDR is associated with lower cardiovascular risk and improved survival. The beneficial effects of VDR activation go far beyond endocrine functions of vitamin D, such as control of secondary hyperparathyroidism. Supplementation with 25(OH)D is not sufficient in the absence of active metabolites of vitamin D. Paricalcitol has demonstrated beneficial effects in both experimental and clinical studies, compared with calcitriol. The activation of specific genes by paricalcitol protects the vascular system from calcification, reduces cardiac and renal renin, decreases inflammation and has renoprotective effects, decreasing proteinuria. Taken together, these results provide a biological basis for the observed reduction of cardiovascular mortality in renal patients, including patients with PTH <150 pg/mL or with hyperphosphatemia (Figure 1). Before paricalcitol can be considered as the first choice for cardiovascular protection in CKD patients as it is for the control of secondary hyperparathyroidism, the beneficial effects of this drug, demonstrated in experimental studies and small clinical trials, must be confirmed in ongoing and future studies

Fig. 1.

Mechanisms of cardioprotection and nephroprotection of paricacitol with experimental and supporting clinical evidence. BNP, brain natriuretic peptide; Ca, calcium; CKD, chronic kidney disease; CV, cardiovascular; HD, haemodialysis; LVH, left ventricular hypertrophy; P, phosphorus; PD, peritoneal dialysis; RAAS, renin–angiotensin–aldosterone system; RCT, randomized clinical trial; TX, renal transplant; VDR, vitamin D receptor.

Fig. 1.

Mechanisms of cardioprotection and nephroprotection of paricacitol with experimental and supporting clinical evidence. BNP, brain natriuretic peptide; Ca, calcium; CKD, chronic kidney disease; CV, cardiovascular; HD, haemodialysis; LVH, left ventricular hypertrophy; P, phosphorus; PD, peritoneal dialysis; RAAS, renin–angiotensin–aldosterone system; RCT, randomized clinical trial; TX, renal transplant; VDR, vitamin D receptor.

Funding

Some of the work cited in this review are granted by the following agencies: ISC III (PI10/00072), RECAVA (RD06/0014/0035;) y European Network (HEALTH F2-2008-200647), Euro Salud EUS2005-03565. cvREMOD (091100) and Fundacion Lilly to J.E. And ISCIII and FEDER funds PS09/00447, ISCIII-RETIC REDinREN/RD06/0016, Comunidad de Madrid/CIFRA, S2010/BMD-2378, Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM) to A.O.

Conflict of interest statement

E.G.P., J.R.R., M.P., A.O. and J.E. are the members of the PALIFE steering committee, a clinical trial assessing the effects of paricalcitol on CKD.

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