Abstract
The relationship between vitamin D and heart structure and function is of crucial importance in chronic kidney disease (CKD) because cardiovascular events including sudden cardiac death are, beside cancer, the major cause of premature mortality in these patients. The vitamin D receptor (VDR) is expressed in the heart and the vessels, and experimental studies have documented various molecular effects of vitamin D that may protect against heart diseases. Epidemiological studies in CKD patients identified vitamin D deficiency as a risk marker for adverse cardiovascular outcomes. Randomized controlled trials (RCT) have shown that vitamin D treatment exerts beneficial effects on some cardiovascular risk factors such as parathyroid hormone and proteinuria, but there was no effect on myocardial hypertrophy. Whether vitamin D treatment can significantly reduce cardiovascular events in CKD patients is still unclear because available data are based on very few and relatively small RCTs. It should, however, be noted that some RCTs including one meta-analysis suggest that patients on active vitamin D treatment experience fewer cardiovascular events. Regarding clinical use of vitamin D in CKD patients, it must therefore be stressed that although patients on active vitamin D treatment are at increased risk of hypercalcemia, there is no clear indication that this potential adverse effect translates into higher cardiovascular risk. These safety considerations are of great importance when considering the clinical use of active vitamin D treatment, but further large RCTs are urgently needed to better characterize the cardiovascular effects of vitamin D treatment in CKD.
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1 Introduction
Cardiovascular events including sudden cardiac death are, beside cancer, the major causes of mortality in chronic kidney disease (CKD) patients [1–3]. There exists a complex interplay between cardiovascular diseases and CKD–mineral and bone disorders (CKD–MBD) which are of great importance for monitoring, treatment, and outcome of CKD patients [4]. In this context, it is classically known that vitamin D effects are crucial for the regulation of calcium and phosphate homeostasis, but accumulating evidence from experimental studies indicates that vitamin D may also participate in the pathogenesis of cardiovascular diseases. In line with this, vitamin D deficiency has also been identified as a risk marker for an adverse cardiovascular risk profile and for increased cardiovascular events and mortality [5, 6]. In this book chapter, we will give an overview on the existing knowledge on vitamin D and cardiovascular disease in CKD with a particular focus on heart structure and function. In addition, we will also briefly summarize data on the relationship between vitamin D and vessel diseases as well as cardiovascular risk factors because heart diseases are frequently the final consequence of these pathologies. Our work is based on a Pubmed literature search until October 2015 using the search terms “vitamin D AND kidney AND cardiovascular” and “vitamin D AND kidney AND heart”. We also checked the reference lists from the identified articles for further relevant literature. We aimed to restrict our work to data in the setting of CKD because general data on vitamin D and cardiovascular diseases have already been well reviewed elsewhere, and vitamin D metabolism in CKD differs significantly from individuals with normal kidney function [7–13]. We refer to the existing literature and to other chapters of this book with regard to basic vitamin D knowledge in CKD patients.
2 Experimental Studies
2.1 VDR Activation and Heart Structure and Function
Expression of the vitamin D receptor (VDR) as well as of 1α-hydroxylase has been identified in the heart and the vessels, i.e. in cardiomyocytes, endothelial cells and vascular smooth muscle cells (VSMC) [14–17]. Main mechanisms for direct vitamin D effects on the myocardium are shown in Fig. 19.1. Knock-out mice for either VDR or 1α-hydroxylase are hypertensive with cardiac hypertrophy that is at least partially induced by overexpression of renin with increased activity of the renin angiotensin aldosterone system (RAAS). Even mice with a cardiomyocyte-specific VDR-knockout yield myocardial hypertrophy [18]. It is well documented in experimental studies that VDR activation suppresses cardiomyocyte hypertrophy, and reduces cell proliferation and atrial natriuretic peptide (ANP) gene expression [19–21]. Consistent with this, it has also been shown that rats on a low vitamin D diet develop myocardial hypertrophy and that treatment with VDR agonists exerts antihypertrophic effects [15, 22]. Interestingly, it has also been reported that calcitriol increases the expression and the activity of the type a natriuretic peptide receptor and may thus exert beneficial effects on cardiovascular health by e.g. increasing the excretion of sodium [23, 24].
Main mechanisms for direct vitamin D effects on the myocardium
VDR activation modulates myocardial contractility probably by regulating calcium flux in the myocardium [5, 25]. Regarding the vitamin D effects on myocardial function, it has been observed that 1α-hydroxylase knockout mice suffer from reduced systolic function that can be restored by calcitriol treatment [26]. Interestingly, VDR knockout mice showed accelerated rates of myocardial contraction and relaxation [27]. The effects of VDR activation on myocardial contractility are thus still puzzling but considering that calcitriol was also able to induce accelerated relaxation of cardiomyocytes, it is conceivable that VDR activation may be important for diastolic function [27]. This is supported by data in 5/6 nephrectomized rats showing that the VDR agonist VS-105 improves, beside ejection fraction and fractional shortening, also the E/A ratio, a routine echocardiographic parameter that is used to classify diastolic function [28].
VDR activation has also been shown to regulate myocardial extracellular matrix (ECM) turnover by effects on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [29]. Whether vitamin D induced regulation of ECM turnover may protect against myocardial fibrosis is, however, still not entirely clear because experimental studies were not fully consistent. While studies in nephrectomized and uremic rats reported on antifibrotic effects of calcitriol and paricalcitol, the opposite, i.e. aggravated fibrosis, has been observed in rats with renal insufficiency that were treated with paricalcitol [30–32]. In murine models of cardiac steatosis, an increase in interstitial fibrosis is, however, observed in VDR knockout mice [33]. Furthermore, it was demonstrated that calcitriol prevents transforming growth factor β1 (TGFβ1) mediated pro-fibrotic changes in primary cardiac fibroblasts [34]. In diabetic rats, calcitriol reduced fibrosis and exerted beneficial effects on cardiac function [35, 36]. Survival rate and cardiac function after experimental myocardial infarction were also reduced in VDR knockout compared to wild-type mice [37]. Moreover, VDR activation protected against myocardial reperfusion injury in mice by reducing oxidative stress, and by inhibition of apoptosis and modulation of autophagy [38]. Apart from this, data from stress-exposed mice suggest that vitamin D signaling may protect against stress-induced deteriorating effects on the heart [39]. We can therefore conclude from these experimental data that VDR signaling is indeed important for the maintenance of a physiologic heart structure and function, but we must be aware that cell culture and animal studies may not adequately reflect the pathophysiology in CKD patients.
3 VDR Activation and Vessels
Excess as well as deficiency of vitamin D can lead to vascular calcification. Historically, it is well known for almost a century that vitamin D intoxication induces hypercalcemia with vascular calcification [7, 40]. High dose calcitriol treatment in subtotally nephrectomized rats leads to an increased aortic calcium and phosphate content and induces an osteoblastic phenotype in VSMC with an up-regulation of proteins regulating mineralization and calcium transport, and of osteogenic transcription factors [7, 41]. VDR activation induced vascular calcification may be induced by rather a systemic than a local effect because calcitriol induced aortic calcification in uremic rats did not differ between VDR knockout and VDR wild-type aortic allografts [42]. It is also important to note that calcitriol induced vascular calcification in rats is reversible after withdrawal of calcitriol [43, 44]. High serum phosphate levels seem to be critical for calcitriol induced vascular calcification because lowering phosphate levels can prevent vascular calcification in klotho knock-out mice, which are characterized by both high calcium and high calcitriol levels [43, 44]. In contrast to calcitriol induced vascular calcification it has also been reported that mice treated with a low vitamin D diet had more aortic calcification and higher expressions of osteogenic key factors than mice fed with recommended amounts of vitamin D [45, 46]. In a mouse model of CKD, calcitriol and paricalcitol protected against aortic calcification at dosages sufficient to correct secondary hyperparathyroidism, whereas higher dosages induced aortic calcification [47]. A molecular effect of VDR activation that may protect against vascular calcification is an increased expression of the anticalcification factor osteopontin as shown in aortic medial cells [48]. The osteogenic process of VSMC mineralisation induced by phosphate and tumor necrosis factor-α (TNF- α) could also be abrogated by VDR agonists [49].
Several experimental studies have, by the majority, shown that vitamin D may protect against endothelial dysfunction and atherosclerosis. VDR agonists improved endothelial function in 5/6 nephrectomized rats and in diabetic rats with early-stage nephropathy [50–52]. Mechanistically, it has been demonstrated that VDR signaling increases NO synthesis and reduces expression of cyclooxygenase-2 (COX-2) and thromboxane-prostanoid receptors [53, 54]. Expression of endothelial adhesion molecules, e.g. ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), is suppressed by VDR activation, and knock-down of the VDR in endothelial cells was associated with endothelial activation characterized by increased leukocyte-endothelial cell interactions [55]. VSMC are also target cells for vitamin D and it has been reported that VDR knockout mice have an increased production of angiotensin-II and superoxide anions leading to premature senescence of VSMC [56]. VDR agonists may also suppress VSMC proliferation, but this has not been consistently reported in all studies [57, 58]. Moreover, calcitriol has been shown to inhibit foam cell formation and cholesterol uptake in macrophages of patients with type 2 diabetes mellitus [59]. Another anti-atherosclerotic effect of VDR activation is mediated by regulation of cholesterol efflux and macrophage polarization as shown in hypercholesterolemic swine [60]. Experimental data also indicate that VDR activation may promote vascular repair [61]
4 VDR Activation and Cardiovascular Risk Factors
Numerous experimental studies have shown that vitamin D may protect against a variety of classic and emerging risk factors. In this context, it must be stressed that the suppression of parathyroid hormone (PTH) is an important cardiovascular-protective effect of VDR activation when considering that PTH itself exerts several harmful effects on the heart and the vessels [62, 63]. Suppression of renin expression and the RAAS by vitamin D has been shown to prevent hypertension, atherosclerosis and heart diseases in experimental studies [14, 64–66]. Several other effects of VDR activation on cardiovascular risk factors such as inflammation, diabetes mellitus, arterial hypertension, blood lipids, coagulation, and renal diseases have been extensively reviewed elsewhere [7–11, 67].
5 Observational Studies
5.1 25-Hydroxyvitamin D and Cardiovascular Disease
Most, albeit not all, epidemiological studies in CKD patients showed that low levels of 25-hydroxyvitamin D (25[OH]D) are associated with an increased risk of cardiovascular disease and mortality including sudden cardiac death [68–80]. In small clinical studies, low serum 25(OH)D concentrations were partially associated with myocardial hypertrophy in CKD patients [81, 82]. Low serum 25(OH)D concentrations were associated with vascular calcification in some but not all studies in CKD patients [83–86]. Several studied in CKD patients showed, however, a significant association between vitamin D deficiency and endothelial dysfunction as well as clinical measures of atherosclerosis [85, 87–89]. It has been largely, but not consistently, observed that low serum 25(OH)D concentrations are associated with albuminuria, and decline of glomerular filtration rate (GFR) including progression to end-stage renal disease [77, 90–95].
6 Calcitriol and Cardiovascular Disease
Epidemiological studies in CKD patients have largely shown that low serum concentrations of calcitriol are associated with an increased risk of mortality and cardiovascular events [61, 66, 70, 88]. In CKD patients with and without dialysis, serum calcitriol levels were either inversely or not associated with vascular calcification and atherosclerosis [76, 78, 89, 90]. Moreover, in patients with advanced kidney disease, low serum calcitriol levels were predictive for initiation of long-term dialysis treatment [78].
7 Vitamin D Genetics and Cardiovascular Disease
In 182 dialysis patients there was a significant association between the Bsml VDR polymorphism and left ventricular mass index [99]. Similar associations have been confirmed in non-dialysis patients [100]. There was, however, no significant association between VDR polymorphisms and end-stage renal disease in a meta-analysis including 1510 patients and 1812 controls [101].
8 Vitamin D Treatment and Cardiovascular Diseases
8.1 Natural Vitamin D Treatment: Observational and Uncontrolled Studies
Some observational studies report on use of natural vitamin D supplements and cardiovascular diseases in CKD [102–113]. It has been observed that ergocalciferol treatment was associated with reduced cardiovascular events in 126 older men with CKD stages 3 and 4 [104]. An observational study in hemodialysis patients reported on significant improvement in left ventricular function (i.e. decreased end-diastolic and end-systolic diameters) in five patients treated with 100 μg 25(OH)D for 8 months when compared to five patients without vitamin D supplementation [105]. A 1-year prospective study in hemodialysis patients showed that oral cholecalciferol supplementation was associated with significantly reduced brain natriuretic peptide (BNP) levels and left ventricular mass index [106]. Another observational study in 30 hemodialysis patients confirmed that oral cholecalciferol supplementation over 6 months was associated with significantly decreased left ventricular mass index, and similar results were also obtained in a further observational study in dialysis patients [107, 108]. Moreover, it has been observed in 15 patients with IgA nephropathy, that parameters of cardiac autonomic tone were significantly improved when comparing values at baseline and 28 days after daily vitamin D supplementation with 10,000 International Units (IU) [109]. In 26 patients with CKD stage 3 and 4 it was reported that after cholecalciferol supplementation of 300,000 IU at baseline and after 8 weeks there was a significant decrease in E-Selectin, ICAM-1, and VCAM-1 at week 16 [110]. A study in 213 hemodialysis patients reported that ergocalciferol treatment is associated with significantly reduced frequency of vascular access dysfunction [111]. Natural vitamin D supplementation was also associated with reductions in inflammatory parameters in several, but not all, observational studies [106–108, 110, 112, 113].
8.2 Natural Vitamin D Treatment: Randomized Controlled Trials
Some randomized controlled trials (RCTs) have already been performed to study cardiovascular effects of natural vitamin D supplementation in CKD patients. A RCT in 84 dialysis patients receiving either 50,000 IU vitamin D per week for 8–12 weeks or placebo failed to show a significant effect on circulating pro-B-type natriuretic peptide (pro-BNP) concentration [114]. In 38 vitamin D deficient patients with CKD stage 3 and 4 who were randomized to either 50,000 IU vitamin D weekly for the first month and then monthly or placebo for an overall study period of 6 months, there were significant improvements in endothelium dependent microcirculatory vasodilatation and pulse pressure, and a reduction in tissue advanced glycation end products in the vitamin D compared to the placebo group [115]. Another RCT was performed in 60 hemodialysis patients who were randomly allocated to 50,000 IU vitamin D or placebo, once weekly for 8 weeks and then monthly for 4 months [116]. There was, however, no significant effect on pulse wave velocity (PWV) in that study [116]. There was also no significant vitamin D effect on left ventricular systolic function, left ventricular diastolic function, BNP, PWV, central blood pressure, 24-h blood pressure, and augmentation index in a RCT in 50 dialysis patients randomized to 3000 IU cholecalciferol daily or placebo for 6 months [117]. A further RCT was performed in 105 hemodialysis patients who received either ergocalciferol 50,000 IU weekly, 50,000 IU monthly or placebo for 1 year [118]. There were, apart from an increase in 25(OH)D, no significant effects on parameters of mineral metabolism or hospitalizations, but there was a non-significant trend towards reduced mortality in patients allocated to ergocalciferol with a hazard ratio (95 % confidence interval) of 0.28 (0.07–1.19). Moreover, there was no effect on arterio-vein access maturation in a cholecalciferol RCT in 52 hemodialysis patients [119]. In 96 hemodialysis patients awaiting transplantation it was evaluated in a RCT whether 50,000 IU cholecalciferol weekly for 1 year prevents alloreactive T-cell memory formation, but there were was no significant effect [120]. Another RCT in 38 hemodialysis patients did also not report on any vitamin D effect on cytokines (CRP and TNF-α), Th1 and Th2 lymphocyte frequencies and monocyte subset cell counts [121]. Regarding effects of vitamin D on vascular calcification in RCTs in CKD patients, it can be summarized that there were no relevant adverse effects but also no significant benefits, and the overall conclusion is that natural vitamin D supplementation is relatively safe in these patients [122, 123]. While it is logical that vitamin D supplementation is effective in increasing serum 25(OH)D levels across all stages of CKD, it has also been shown that PTH can also be suppressed by natural vitamin D treatment, albeit this has not been consistently confirmed in all RCTs [122–128]. Vitamin D RCT data in CKD patients on other cardiovascular risk factors such as e.g. glucose metabolism or blood pressure are sparse and did largely show no consistent and significant effect [102, 103]. Most studies performed in study cohorts without CKD did also fail to prove a significant blood pressure reduction by natural vitamin D supplementation [129, 130].
9 Active Vitamin D Treatment: Observational and Uncontrolled Studies
Since there are several RCTs published on active vitamin D treatment and cardiovascular diseases and its risk factors we just briefly mention some of the epidemiological studies on this topic. In this context, several observational studies have, by the majority, reported that the use of active vitamin D and its analogues is associated with significantly reduced risk of cardiovascular events and mortality [68, 96, 98, 131–150]. Some, albeit not all, observational or uncontrolled studies in CKD patients revealed that active vitamin D treatment is associated with improved left ventricular function, regression of myocardial hypertrophy, and reduction of QTc interval and dispersion [141–148]. Data on active vitamin D treatment and vascular calcification are sparse, but one study in 36 dialysis patients comparing low-dose versus high-dose calcitriol treatment for 1 year did not find any significant difference in vascular calcification [149]. Other studies, however, showed that prescription of active vitamin D treatment is associated with increased vascular calcification and vascular stiffness [150–152]. In contrast, active vitamin D treatment was associated with beneficial effects on parameters related to calcification and may thereby possibly protect against vascular damage [153–155]. Regarding observational studies on cardiovascular risk factors, it should be noted that active vitamin D treatment is, beyond its suppressive effects on PTH, associated with reduced proteinuria and anti-inflammatory effects in some, but not all, investigations [156–158]. It is also important to note that active vitamin D treatment causes an increase in creatinine generation without affecting glomerular filtration rate (GFR) [159].
9.1 Active Vitamin D Treatment: Randomized Controlled Trials
Two meta-analyses of RCTs have already addressed the research question on whether active vitamin D treatment has an effect on cardiovascular outcomes [160, 161]. Li et al. investigated the question whether active vitamin D analogues in predialysis CKD patients have an effect on cardiovascular events [161]. Five RCTs in 715 patients who experienced 35 cardiovascular events during a follow-up time of 16 weeks to 52 weeks were included into the meta-analysis [161]. As the main outcome, active vitamin D treatment was associated with a significantly reduced relative risk (RR) of 0.27 (95 % confidence interval [CI]: 0.13–0.59; p = 0.001) for cardiovascular events. In the same meta-analysis, active vitamin D treatment was also associated with reduced proteinuria, but there was no effect on left ventricular mass index, left ventricular systolic function, and systolic and diastolic blood pressure. There was, however, a significantly increased risk of hypercalcemia (i.e. serum calcium concentrations above 11.0 mg/dL [2.75 mmol/L]) associated with paricalcitol treatment with a RR (95 % CI) of 7.85 (2.92–21.1; p < 0.001). While the main outcome of this meta-analysis, i.e. the significant reduction of cardiovascular events, suggests cardiovascular benefits of active vitamin D analogues, it must be acknowledged that this study is clearly limited by the relatively low number of events [161]. Another meta-analysis of RCTs by Mann et al. addressed the question whether vitamin D treatment (with either active or natural vitamin D) in patients with CKD has an effect on all-cause mortality, cardiovascular mortality, and serious adverse cardiovascular events [160]. For the main outcome all-cause mortality, 13 trials in 1469 patients with 41 fatal events and a follow-up of 3–104 weeks were included, with the vast majority of patients in RCTs on active vitamin D treatment. There was no significant effect of vitamin D treatment on all-cause mortality with a RR (95 % CI) of 0.84 (0.47–1.52). Data on cardiovascular mortality were identified in 6 RCTs in 937 patients with 8 events and a RR (95 % CI) of 0.79 (0.26–2.28). Data on serious adverse cardiovascular events were identified in 8 RCTs in 1217 patients with 15 events and a RR (95 % CI) of 1.20 (0.49–2.99). The meta-analysis by Mann et al. was thus based on fewer cardiovascular events compared to the more recent meta-analysis by Li et al. Regarding the conclusions drawn from these meta-analyses it should be noted that the RCTs included were, in general, not a priori designed to evaluate cardiovascular events and that the low event rate is a clear limitation. It was thus concluded by Mann et al. that “the current state of the literature is unfit to systematically quantify any effect of vitamin D therapy on mortality and cardiovascular events” [160].
Specific effects of paricalcitol on myocardial structure and function have been evaluated in the PRIMO (Paricalcitol Capsule Benefits in Renal Failure-induced cardiac Morbidity) trial [162, 163]. In that RCT, 227 patients with CKD (GFR: 15–60 mL/min/1.73 m2) and preserved left ventricular ejection fraction with mild to moderate left ventricular hypertrophy, were randomly assigned to receive paricalcitol 2 μg daily (n = 115) or placebo (n = 112). The primary end point was change in left ventricular mass index at 48 weeks and secondary end points included measures of left ventricular diastolic and systolic function, cardiac volume indexes, cardiovascular events and cardiac biomarkers. The main outcome of the PRIMO trial was that paricalcitol did not reduce left ventricular mass index. Considering that the CI was narrow and that there was a marked decrease in PTH, suggesting a strong physiologic effect of paricalcitol, the authors concluded that even a larger sample size would have yielded similar results. While there were also no meaningful effects on most secondary outcomes, there was a significantly reduced risk of cardiovascular hospitalizations in the paricalcitol (n = 1) versus the placebo group (n = 8) (p = 0.04). In a post-hoc analysis of the PRIMO trial restricted to 196 patients with available echocardiographic data, it has been shown that left atrial volume index, a measure of diastolic dysfunction severity that indicates a higher cardiovascular risk, was significantly reduced after 48 weeks in the paricalcitol group (−2.97 mL/m2, 95 % CI: −4.00 to −1.59 mL/m2) compared to the placebo group (−0.70 mL/m2; 95 % CI: −1.93 to 0.53 mL/m2; p = 0.002) [163]. The rise in BNP throughout the PRIMO trial was also significantly attenuated in the paricalcitol (+8.4 pg/mL) versus the placebo group (+18.5 pg/mL; p = 0.02). These effects of paricalcitol on left atrial volume index and BNP are remarkable when considering that there was a similar blood pressure control in both groups and that RAAS inhibitor use was 80 %. It should also be noted that the effect of paricalcitol was homogeneous across all subgroups and that the changes in left atrial volume index paralleled the attenuation in BNP. Another RCT, the OPERA trial, on paricalcitol and left ventricular mass index as the primary outcome has been performed in 60 patients with CKD stage 3–5 and left ventricular hypertrophy [164]. Thirty patients were randomized to paricalcitol 1 μg daily and 30 patients to placebo. After 52 weeks, there was no significant difference in left ventricular mass index in the paricalcitol compared to the placebo group. Secondary outcome measures of left ventricular systolic and diastolic function did also not differ between the groups. Therefore, the results of the RCT by Wang et al. confirm the findings from the PRIMO trial by showing no effect of active vitamin D treatment on myocardial hypertrophy in a cohort with more severe CKD and secondary hyperparathyroidism when compared to the PRIMO study cohort. Interestingly, Wang et al. recorded two patients with hosptialization in the paricalcitol, and ten patients who were hospitalized in the placebo group (p = 0.02). Notably, no patient in the paricalcitol group had a cardiovascular-related hospitalization, whereas there were five patients with such an event in the placebo group.
Two further RCTs showed some beneficial effects of paricalcitol treatment on endothelial function [165, 166]. Zoccali et al. evaluated in a RCT in 88 patients with CKD stage 3–4 and a PTH greater than 65 pg/mL, the effect of paricalcitol 2 μg daily for 12 weeks on endothelium-dependent and endothelium-independent vasodilatation [166]. After 12 weeks, flow-mediated dilatation was significantly better in the paricalcitol compared to the placebo group, but there was no significant difference for endothelium-independent vasodilatation. A further RCT was conducted in 36 non-diabetic patients with CKD stage 3–4 who were randomly allocated to paricalcitol 2 μg daily (n = 12), paricalcitol 1 μg daily (n = 12), or placebo (n = 12) for 3 months [165]. Outcome measures were parameters of sympathetic activation, macro- and microvascular functions. While most outcome measures were not affected by treatment, there was a significant decline in endothelial function in all groups, except the 2 μg paricalcitol group.
Several trials evaluated the effects of active vitamin D treatment on proteinuria [167–173]. The meta-analyses in this field found that active vitamin D treatment decreases proteinuria significantly. These findings have been well reviewed elsewhere [168–173].
Some other studies have also investigated the impact of active vitamin D therapy on glucose metabolism but the results were mixed. Regarding other cardiovascular risk factors it should be noted that there were e.g. no consistent and relevant effects on blood pressure [174].
The beneficial effects of active vitamin D treatment on PTH and some parameters of bone and mineral metabolism have also been evaluated in RCTs, and it has been clearly shown that active vitamin D treatment suppresses PTH and some bone markers such as bone alkaline phosphatase [171, 175, 176]. The clinical relevance of the interaction between vitamin D and fibroblast growth factor 23 (FGF23) as well as the significance of FGF23 in the pathogenesis of cardiovascular diseases still need to be further studies [13].
Several studies, on active as well as on natural vitamin D supplementation, are still ongoing in CKD patients and will hopefully help to clarify the role of vitamin D treatment for heart structure and function [176–181].
10 Conclusions
While there is compelling evidence from experimental and observational studies indicating that vitamin D may exert beneficial effects on myocardial structure and function, there are only very few and limited data addressing these issues in RCTs in CKD patients. Based on the available evidence it is thus premature to draw firm and definite conclusions on the effects of vitamin D treatment on heart structure and function in CKD. In particular, RCT data on natural vitamin D treatment in CKD are sparse, whereas there are already some RCT data available on active vitamin D treatment. Results derived from the PRIMO study on improvements in left atrial volume index and serum BNP levels by paricalcitol treatment are promising regarding potential beneficial effects of active vitamin D treatment on heart structure and function, but these findings need further confirmation in future RCTs. It should, however, be noted that although data on hard cardiovascular endpoints are sparse and limited by low event rates, some RCTs including one meta-analysis of RCTs suggest that patients on active vitamin D treatment experience fewer cardiovascular events. Further large RCTs are therefore needed to address the question whether vitamin D treatment is clinically indicated to prevent and treat cardiovascular diseases in CKD patients. The currently available data suggesting reduced cardiovascular events in CKD patients on active vitamin D treatment (i.e. paricalcitol) are a scientifically sound rationale for further RCTs addressing the impact of active vitamin D treatment on cardiovascular events as a primary outcome. Regarding the current relatively widespread use of vitamin D in CKD patients, it must also be stressed that although patients on active vitamin D treatment are at increased risk of hypercalcemia, there is no clear indication from RCTs that this adverse effect of active vitamin D treatment translates into higher cardiovascular risk since the available literature suggests that cardiovascular events and mortality are rather reduced than increased with active vitamin D treatment. Therefore, while proposed beneficial effects of active vitamin D treatment on heart structure and function still need to be further evaluated, the evidence from RCTs is quite convincing that active vitamin D treatment, at doses commonly used in clinical practice, is not harmful for the heart. These safety considerations are of great importance when considering the use of active vitamin D treatment in CKD patients.
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Pilz, S., Brandenburg, V., Ureña Torres, P.A. (2016). Vitamin D and Heart Structure and Function in Chronic Kidney Disease. In: Ureña Torres, P., Cozzolino, M., Vervloet, M. (eds) Vitamin D in Chronic Kidney Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-32507-1_19
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