NDT Advance Access published online on November 7, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn624
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Association of oral calcitriol with improved survival in non-dialyzed and dialyzed patients with CKD
Instituto de Investigaciones Metabólicas, Universidad del Salvador School of Medicine, Buenos Aires, Argentina
Correspondence and offprint requests to: Armando Luis Negri, Instituto de Investigaciones Metabólicas, Libertad 836 1 piso, Buenos Aires 1012, Argentina. Tel: +54-1-50319700; Fax: +5411-4633-3838, Ext. 220; E-mail: negri{at}casasco.com.ar
Keywords: haemodialysis; oral calcitriol; predialysis; survival
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Introduction |
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A large body of evidence suggests that vitamin D has health benefits beyond its central role in calcium-phosphorus homeostasis, regulation of PTH and formation and maintenance of bone [1]. Activated vitamin D binds to the vitamin D receptor (VDR) and influences diverse genetic responses in many tissues. This is because VDR is expressed not only in the classical target organs (bone, parathyroid glands, kidneys and intestine) but also in other non-classical targets including arteries, heart, immune system, endocrine organs and even the nervous system [1].
Vitamin D can inhibit various aspects of inflammation, which have been established as a key pathogenic mechanism in atherosclerosis: Vitamin D through VDR activation increases the Th2 cell population of lymphocytes [2]. Th2 lymphocytes are antiatherogenic through their production of IL-10 [3] that is upregulated by calcitriol [4], inhibiting macrophage activation. Calcitriol also inhibits interferon gamma that is a potent activator of macrophages [5], which is secreted by Th1 lymphocytes that infiltrate the subendothelial space of vessels in response to oxidized low-density lipoproteins. VDR activation also stimulates IL-4 synthesis that is important in promoting the antiatherogenic function of Th2 cells. Another mechanism by which VDR activation can prevent complications of the atheromatous plaques is through the prevention of the thromboses demonstrated in VDR knockout mice that develop arterial thromboses in association with downregulation of antithrombin and thrombomodulin and upregulation of tissue factor [5].
Vitamin D exerts an antiproliferative effect on many cell types including myocardial cells. Myocardial cell hypertrophy and proliferation underlies the pathogenesis of congestive heart failure. Treatment with calcitriol decreases endothelium-induced atrial natriuretic peptide levels while ameliorating cardiac myocyte hypertrophy [6]. VDR activation downregulates atrial natriuretic peptide transcription by nuclear interactions that do not involve retinoid X receptor-VDR heterodimerization [7,8]. Vitamin D acts as a negative endocrine regulator for the renin–angiotensin system, which plays an important role in hypertension and cardiovascular health [9]. Mice lacking the VDR have elevated production of renin and angiotensin (Ang) II, leading to hypertension, cardiac hypertrophy and increased water intake. These abnormalities can be prevented by treatment with an ACE inhibitor or AT [1] receptor antagonist. Vitamin D repression of renin expression is independent of calcium metabolism, the volume- and salt-sensing mechanisms and the Ang II feedback regulation. In normal mice, vitamin D deficiency stimulates renin expression, whereas injection of calcitriol reduces renin synthesis. In cell cultures, calcitriol directly suppresses renin gene transcription by a VDR dependent. Low serum levels of vitamin D have also been associated with impaired glucose tolerance and diabetes across diverse populations and administration of vitamin D3 to deficient animals improves insulin secretion [10,11].
Chronic kidney disease (CKD) patients have an increased risk of cardiovascular disease (CVD) and mortality compared with healthy individuals, most likely due to the presence of severe atherosclerosis and accelerated vascular calcification. Vascular calcification is an active, regulated process resulting from an imbalance between the loss of inhibitory factors and the increase in inducing factors present both in vessels and the circulation. However, exactly which inhibitory and inducing factors are involved remains controversial. Several VDR activators (VDRAs), including paricalcitol and calcitriol, currently used for the treatment of secondary hyperparathyroidism in patients with CKD have shown survival benefits in CKD patients independent of serum parathyroid hormone, phosphorus and calcium levels. The survival benefit of VDRAs seems contradictory to the perception that VDRAs, due to their potential impact of increasing serum phosphorus and calcium, may cause vascular calcification. Inconsistent data exist regarding the role of VDRAs in vascular calcification. A possible explanation is that the VDR may be involved in regulating several different pathways as an endocrine, paracrine and/or autocrine factor, and different VDRAs may have differential effects on the endocrine versus the paracrine/autocrine aspect. An inverse relationship between arterial calcifications and bone activity has also been documented in patients with ESRD. A significant interaction was found between dosage of calcium-containing phosphate binders and bone activity such that calcium load had a significantly greater influence on aortic calcifications and stiffening in the presence of adynamic bone disease. Independent of any other factor, including dosage of calcium-containing phosphate binders, adynamic bone was associated with greater aortic stiffening. [12] High doses of calcitriol administered for prolonged periods, as used for the treatment of secondary hyperparathyroidism, can induce adynamic bone disease. Despite this, a recent prospective study did not find an association between calcitriol administered doses and the progression of vascular calcification [13].
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Parenteral administration of VDRAs and survival |
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Parenteral vitamin D has been associated with improved survival among long-term haemodialyzed patients. In a retrospective study, patients who received injectable vitamin D (either calcitriol or paricalcitol) had a 20–25% higher survival rate than those who did not receive injectable vitamin D over the same period of time [14]. All-cause mortality, as well as cardiovascular mortality, was less in the group receiving injectable vitamin D after adjusting for potential confounders. In another study, Tentori et al. assessed mortality associated with different vitamin D analogues and with the lack of vitamin D therapy in patients who began HD [15]. In unadjusted models, mortality was lower in patients on doxercalciferol and paricalcitol versus calcitriol, but in adjusted models, this difference was not statistically significant. In all models mortality was higher for patients who did not receive vitamin D versus those who did.
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Oral administration of calcitriol and improved survival |
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Although oral active vitamin D treatment is widely used around the world, until recently there was only one communication of survival in a small haemodialysis population using oral active vitamin D compounds. Shoji et al. [16] found that patients on a low-dose oral alfacalcidol had a significantly lower risk for cardiovascular death than those without vitamin D supplementation.
Three recent papers have shown that oral calcitriol even in low doses (<1 mcg) reduced overall and cardiovascular mortality in predialysis and haemodialized patients.
Kovesdy et al. [17] examined the association of oral calcitriol treatment with mortality and the incidence of dialysis in 520 old male US veterans with CKD stages 3–5 and not yet receiving dialysis with an estimated glomerular filtration rate of 30.8 ml/min. Associations were adjusted for age, race and comorbidities. Two hundred fifty-eight of 520 subjects received treatment with calcitriol, 0.25–0.5 mcg/day, for a median duration of 2.1 years (range, 0.06–6.0 years). The incidence rate ratios for mortality and combined death and dialysis initiation were significantly lower in those treated with oral calcitriol versus the untreated patients (P < 0.001 for both in the fully adjusted models). The results were consistent across different subgroups. Treatment with calcitriol was also associated with a trend towards a lower incidence of dialysis. This tendency towards a lower incidence of ESRD in the calcitriol-treated group, which makes it unlikely that such therapy is as deleterious as in high doses [18], raises the possibility that calcitriol has a renoprotective effect as has been previously suggested [19]. Such an effect is conceivable because therapy with paricalcitol has been shown to lower proteinuria [20] and suppress the progression of renal insufficiency via mediation of the TGF-beta signalling pathway, and this effect is amplified when associated with renin–angiotensin system blockade [21].
A similar study evaluated associations of oral calcitriol use with mortality and dialysis dependence in 1418 non-dialysis patients with CKD and hyperparathyroidism [22]. The authors abstracted the data from the Northwest Veterans’ Affairs Consumer Health Information and Performance Sets (CHIPS) database. They focus on calcitriol as this medication is commonly prescribed in CKD and could be accurately ascertained from pharmacy records. Incident calcitriol users and nonusers were selected on the basis of stage 3–4 CKD, hyperparathyroidism and in the absence of hypercalcaemia before calcitriol use and then were matched by age and estimated kidney function. During a median follow-up of 1.9 years, 408 (29%) patients died and 217 (16%) initiated long-term dialysis. After adjustment for demographics, comorbidities, estimated renal function, medications and baseline levels of parathyroid hormone, calcium and phosphorous, oral calcitriol use was associated with a 26% lower risk for death (95% CI 5–42% lower; P = 0.016) and a 20% lower risk for death or dialysis (95% CI 1–35% lower; P = 0.038). The association of calcitriol with improved survival was not statistically different across baseline parathyroid hormone levels. The use of calcitriol was associated with a greater risk for hypercalcaemia. The primary limitation of this study was the potential for confounding by indication, although the authors used a number of techniques to address this problem.
Finally, a recent paper addressed the use of oral calcitriol use on the survival of haemodialysis patients [23]. The authors determined the survival benefit of oral active vitamin D in haemodialysis patients from six Latin America countries (FME Register(R) as part of the CORES study) followed for a median of 16 months. Time-dependent Cox regression models, after adjustment for potential confounders, showed that the 7203 patients who received oral active vitamin D had significant reductions in overall, cardiovascular, infectious and neoplastic mortality compared to the 8801 patients that had not received vitamin D. Stratified analyses found a survival advantage in the group that had received oral active vitamin D in 36 of the 37 strata studied including that with the highest levels of serum calcium, phosphorus and parathyroid hormone. Multivariable adjusted analyses revealed that patients who received oral active vitamin D had a significant 45% (HR 0.55; 95% CI 0.49–0.63) lower mortality risk compared to patients who did not receive oral active vitamin D. Reductions in mortality risk were similar for cardiovascular, infectious and neoplastic causes. The survival benefit of oral active vitamin D was seen in those patients receiving mean daily doses of <1 mcg with the highest reduction associated with the lowest dose (<0.25 mcg). The reduction in mortality risk was seen even in the lowest PTH tertile, where a tendency to a higher mortality has been described. Survival benefit was also seen in patients with high serum phosphorus levels, in which mortality has been shown to be higher. Survival results were consistent in all centres and across countries despite the differences in mortality rates among them. As in the previous study, the risk of confounding by indication cannot be ruled out.
The biggest limitation of these studies with oral calcitriol has been their observational nature of them. These studies have also overlooked 25(OH)D3 levels in their patients. Observational data suggest that low 25-hydroxyvitamin D levels (25[OH]D) are associated with diabetes mellitus, hypertension and cancers. Melamed et al. [24] recently tested the association of low 25(OH)D levels with all-cause, cancer and CVD mortality in 13 331 adults who were 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files. They found that the lowest quartile of the 25(OH)D level (<17.8 ng/ml) was independently associated with all-cause mortality in the general population. If this is true also for patients with CKD, would the correction of serum 25(OH)D reduce mortality in the same way as low doses of calcitriol? Prospective randomized clinical trials are required to verify the causality of these associations and to examine whether similar associations are seen with different oral non-activated and activated vitamin D analogues. There is also a need to determine if vitamin D should be administered to all patients with CKD, not only to those with secondary hyperparathyroidism, and which is the lowest dose of these compounds that offers survival advantage with the lowest incidence of side effects.
Conflict of interest statement. None declared.
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[Abstract/Free Full Text]
Accepted in revised form: 15.10.08
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