No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Vitamin D Receptor Polymorphism in Chronic Kidney Disease Patients With Complicated Cardiovascular Disease
Abstract
Several studies indicate a relationship between vitamin D and cardiovascular disease. Pleiotropic actions of vitamin D and its analogs are mediated by vitamin D receptor (VDR). VDRs have been identified in almost all tissues, including vascular smooth muscle cells, cardiomyocytes, and endothelial cells. The FokI and BsmI polymorphisms of the VDR gene are regarded as strong markers of disturbed vitamin D signaling pathway. Studies investigating the relationship between VDR genotypes and left ventricular hypertrophy revealed a highly significant association with the BsmI Bb heterozygous genotype. There are conflicting data on the action of vitamin D in left ventricular hypertrophy. Experimental as well as observational studies and small clinical trials have suggested that vitamin D administration may favorably influence left ventricular hypertrophy, whereas large randomized clinical trials have shown negative results. However, a beneficial effect on the left atrial volume index and the duration of hospitalization were observed in patients treated with vitamin D analogs. Larger clinical trials with robust clinical end points are needed to confirm that vitamin D is effective in preventing cardiovascular disease in chronic kidney disease patients and in general population.
Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
... The FokI and BsmIpolymorphisms of the vitaminD receptor gene are regarded as strong markers of disturbed of vitamin D signaling pathway [23]. ...
... Some studies have been conducted in chronic renal failure and hemodialysis patients in order to investigate any relation between PTH levels and VDR polymorphisms and it was found that the allele B of the VDR BsmI polymorphism has been associated with protection against end stage renal failure. Also, BsmI gene polymorphism seemed to be associated with PTH function; as levels of the intact PTH were found lower in patients with BB genotype than those with Bb or bb genotypes [23,24]. ...
... Conversely, Fernandez et al. [23], reported that the BB genotype and the B allele were signi icantly more frequent in Spanish patients with end-stage renal disease with low iPTH levels than in patients with high iPTH levels (32.3% versus 12.5% and 58.8% versus 39.1%; respectively). ...
... Commonly studied VDR SNPs include FokI (rs2228570), ApaI (rs7975232), BsmI (rs1544410), and TaqI (rs731236). Of these polymorphisms, ApaI and BsmI are located in the intron between exon 8 and exon 9, FokI is present in exon 2, and TaqI is located in exon 9 (Fig. 4B) [60]. ...
Osteoporosis is a prevalent bone disorder characterized by low bone mineral density (BMD) and deteriorated bone microarchitecture, leading to an increased risk of fractures. Vitamin D (VD), an essential nutrient for skeletal health, plays a vital role in maintaining bone homeostasis. The biological effects of VD are primarily mediated through the vitamin D receptor (VDR), a nuclear receptor that regulates the transcription of target genes involved in calcium and phosphate metabolism, bone mineralization, and bone remodeling. In this review article, we conduct a thorough literature search of the PubMed and EMBASE databases, spanning from January 2000 to September 2023. Utilizing the keywords “vitamin D,” “vitamin D receptor,” “osteoporosis,” and “therapy,” we aim to provide an exhaustive overview of the role of the VD/VDR system in osteoporosis pathogenesis, highlighting the most recent findings in this field. We explore the molecular mechanisms underlying VDR’s effects on bone cells, including osteoblasts and osteoclasts, and discuss the impact of VDR polymorphisms on BMD and fracture risk. Additionally, we examine the interplay between VDR and other factors, such as hormonal regulation, genetic variants, and epigenetic modifications, that contribute to osteoporosis susceptibility. The therapeutic implications of targeting the VDR pathway for osteoporosis management are also discussed. By bringing together these diverse aspects, this review enhances our understanding of the VD/VDR system’s critical role in the pathogenesis of osteoporosis and highlights its significance as a potential therapeutic target.
... Vitamin D is well known for its role in regulating bone health and calcium metabolism. Recent studies have shown that vitamin D is involved in a wide range of pleiotropic functions mediated through vitamin D receptors [71], such as the modulation of cell growth and differentiation [72] and the regulation of immune functions [73], providing a protective effect against diabetes and cardiovascular disease [74]. In kidney transplant recipients, vitamin D may regulate the immune response and protect against cardiovascular disease, cancer, and infection [75]. ...
Kidney transplant recipients are a unique subgroup of chronic kidney disease patients due to their single functioning kidney, immunosuppressive agent usage, and long-term complications related to transplantation. Post-transplant diabetes mellitus (PTDM) has a significant adverse effect on renal outcomes in particular. As transplantations enable people to live longer, cardiovascular morbidity and mortality become more prevalent, and PTDM is a key risk factor for these complications. Although PTDM results from similar risk factors to those of type 2 diabetes, the conditions differ in their pathophysiology and clinical features. Transplantation itself is a risk factor for diabetes due to chronic exposure to immunosuppressive agents. Considering current evidence, this article describes the risk factors, pathogenesis, diagnostic criteria, prevention strategies, and management of PTDM. The therapeutic options are discussed regarding their safety and potential drug–drug interactions with immunosuppressive agents.
... In addition, previous studies have shown an association between FokI and BsmI polymorphisms of the vitamin D gene (VDR) with cardiovascular disease and left ventricular hypertrophy. Moreover, the findings showed that different genetic models of TaqI (rs731236), BsmI (rs1544410), and Cdx2 (rs11568820) polymorphisms of functional variants of the VDR gene are linked to a decreased risk of nonHodgkin's lymphoma (NHL) in the studied population (15,16). Finally, the aforementioned data showed that VDR might play an important role in urolithiasis pathogenesis. ...
Background: Due to the lack of research on pediatric urolithiasis (PU) in Iran, this case-control study aimed to assess the correlation of vitamin D receptor (VDR) gene polymorphisms in the Iranian population living in Kerman, Iran. Methods: This study was conducted on 90 outpatients with urinary calculi (49 female and 41 male subjects with a mean age of 4.55 ± 3.005 years) and 90 healthy children (39 female and 51 male subjects with a mean age of 5.6 ± 3.67 years) without a history of urolithiasis as the control group. Deoxyribonucleic acid was extracted from the blood samples of all patients and healthy subjects, and TaqI genotyping was performed via the restriction fragment length polymorphism method. Results: TaqI single-nucleotide polymorphisms (rs731236) were shown to be associated with a higher incidence of PU. Multivariable logistic regression analysis demonstrated that carriers with the C allele of TaqIrs731236 had a considerably higher risk of PU than the control group (odds ratio = 1.94; 95% confidence interval = 1.24 - 2.96; P = 0.004). Conclusions: The obtained findings demonstrated that C allele (rs731236) and CC variant genotypes were considerably linked with a higher risk of PU in children in the Iranian population.
... It is well-known that VDR is variable across human populations. Several single nucleotide polymorphisms (SNPs) have been described, some of them (e.g., rs1544410, rs731236, rs2228570, and rs7975232, also known as BsmI, TaqI, FokI, and ApaI, respectively) because they are associated with several phenotypes of interest (bone mineral density, protection/susceptibility from ovarian and breast cancer, among others) (Alizadeh, Djafarian, Alizadeh, Mohseni, & Shab-Bidar, 2017;Nunes et al., 2016;Santoro et al., 2015). Hochberg and Templeton (2010) proposed that VDR alleles belong to the evolutionary complex that adapts humans to UVR to the different exposure levels. ...
We carried out an exhaustive review regarding human skin color variation and how much it may be related to vitamin D metabolism and other photosensitive molecules. We discuss evolutionary contexts that modulate this variability and hypotheses postulated to explain them; for example, a small amount of melanin in the skin facilitates vitamin D production, making it advantageous to have fair skin in an environment with little radiation incidence. In contrast, more melanin protects folate from degradation in an environment with a high incidence of radiation. Some Native American populations have a skin color at odds with what would be expected for the amount of radiation in the environment in which they live, a finding challenging the so-called "vitamin D-folate hypothesis." Since food is also a source of vitamin D, dietary habits should also be considered. Here we argue that a gene network approach provides tools to explain this phenomenon since it indicates potential alleles co-evolving in a compensatory way. We identified alleles of the vitamin D metabolism and pigmentation pathways segregated together, but in different proportions, in agriculturalists and hunter-gatherers. Finally, we highlight how an evolutionary approach can be useful to understand current topics of medical interest. K E Y W O R D S co-evolution, gene network, native Americans, skin color, vitamin D
... The VDR gene is located in chromosomal region 12q12.14 and is composed of eight exons coding for proteins (exons 2-9) and of six nontranslated, alternately spliced exons 9 . Hence, more than 25 genetic variants of VDR are possible, among which those caused by single-nucleotide polymorphisms (SNPs) may have significant consequences for health 10 . ...
The objective of this review was to investigate the effect of vitamin D3 supplementation on serum 25-hydroxyvitamin D concentration in individuals with single-nucleotide polymorphisms in the vitamin D receptor gene. The research was conducted on 241 articles found in the PubMed, Scopus, Science Direct, and Cochrane Library databases between November and December 2018. After article screening, three randomized double-blind placebo-controlled clinical trials were identified as eligible for this review. Participants were Australian, Brazilian, and Chinese individuals, who ingested doses of vitamin D3 ranging from 2000 IU to a megadose of 200,000 IU. The presence of the BB/Bb genotype of the BsmI polymorphism and the FokI G allele caused an increase in the serum concentrations of vitamin D after supplementation. Nonetheless, the few studies on this subject are not unanimous in their results. It is possible that differences among populations, sample sizes, doses, and time of supplementation have an impact on data and outcomes.
... Calcium levels rise after Vitamin D taking, leading, on its own, to myocardial hypertrophy, cardiomyocyte apoptosis and heart arrhythmia [32]. Recent findings showing Vitamin D's influence on the left ventricle hypertrophy are not conclusive and representative of its role from the favorable to adverse effect spectrum [33]. ...
Abstract. The article presents an analysis of the recent scientific findings on vitamin D status in patients with different etiopathogene tic varieties of nontraumatic transient loss of consciousness. The results of recent researches suggest that vitamin D may play an indirect and, in some cases, direct role in the pathogenesis of nontraumatic transient loss of consciousness. Data on the causeeffect relationship between a low vitamin D status and syncope are mixed, controversial and ambiguous, which is largely due to the use of different doses of vitamin D, its initial concentration, duration of therapy, genetic diffe rences in the vitamin D receptors, different age groups, physical parameters of the surveyed, medications, peculiarities of nutrition with special supplements, differences in physical activity, peculiarities of the climate and season, and others. Until now there is no convincing evidence of the benefits of using vitamin D in the treatment and prevention of syncope. Most studies are observational and relate mainly to adult populations. Therefore, randomized controlled studies focused on children may be a promising field of research.
(PDF) Vitamin D status in patients with nontraumatic transient loss of consciousness (literature review). Available from: https://www.researchgate.net/publication/337751886_Vitamin_D_status_in_patients_with_nontraumatic_transient_loss_of_consciousness_literature_review [accessed Mar 26 2020].
... That's why one might even has an asymptomatic infection if challenged with a virulent strain. The human VDR gene is located on chromosome 12, which has 8 coding and 3 non-coding regions (Santoro et al. 2015). The most studied VDR gene polymorphisms in the various diseases were ApaI, BsmI, TaqI and FokI (Rashedi et al. 2014). ...
Leishmania, an obligate intracellular parasite is eliminated by a strong Th-1 host response. As Vitamin D metabolism and its receptor activity are important factors in human native immune system against some microorganisms, we hypothesized that VDR gene polymorphisms and concentration of Vitamin D might have effect on incidence of cutaneous leishmaniasis. The aim of this study was to investigate the association between VDR gene polymorphism and/or the serum vitamin D level and leishmaniasis in the infected patients in comparison to the healthy individuals. In this case–control study, the BsmI, FokI and Taq1 polymorphisms in the VDR gene and serum levels of vitamin D were studied in Iranian infected with Leishmania tropica (n = 50) and healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) and Electrochemiluminescence methods respectively. Data were statistically analyzed using SPSS software, Chi square and ANOVA tests. The results of this study showed that despite the relatively higher frequency of BsmI-BB, FokI-FF and TaqI-Tt than Non BsmI-BB, Non FokI-FF and Non TaqI-Tt in the patients compared with the healthy individuals, the differences were not statistically significant (P > 0.05). Based on our findings, the relationship between the VDR polymorphism, the serum concentration of 25-hydroxyvitamin D and the susceptibility to Leishmania tropica infection, remains unclear requiring further in-depth studies. However, for better interpretation, it is necessary to consider factors such as the size of the sample examined and the other alleles of VDR, including ApaI.
... Vitamin D belongs to a family of steroid fat-soluble hormones with a wide range of pleiotropic functions [1]. Its essential role in promoting bone health and calcium homeostasis is well known; beyond these classical functions, burgeoning evidence has shown new health benefits associated with adequate vitamin D metabolism, such as the modulation of cellular growth and differentiation, the regulation of innate and adaptive immune functions [2], a protective effect against diabetes and cardiovascular disease [3] and a much broader range of biological features. ...
Diabetes mellitus (DM) poses a major public health problem worldwide, with ever-increasing incidence and prevalence in recent years. The Institute for Alternative Futures (IAF) expects that the total number of people with type 1 and type 2 DM in the United States will increase by 54%, from 19,629,000 to 54,913,000 people, between 2015 and 2030. Diabetic Nephropathy (DN) affects about one-third of patients with DM and currently ranks as the first cause of end-stage kidney disease in the Western world. The complexity of interactions of Vitamin D is directly related with progressive long-term changes implicated in the worsening of renal function. These changes result in a dysregulation of the vitamin D-dependent pathways. Various studies demonstrated a pivotal role of Vitamin D supplementation in regression of albuminuria and glomerulosclerosis, contrasting the increase of glomerular basement membrane thickening and podocyte effacement, with better renal and cardiovascular outcomes. The homeostasis and regulation of the nephron’s function are absolutely dependent from the cross-talk between endothelium and podocytes. Even if growing evidence proves that vitamin D may have antiproteinuric, anti-inflammatory and renoprotective effects in patients with DN, it is still worth investigating these aspects with both more in vitro studies and randomized controlled trials in larger patient series and with adequate follow-up to confirm the effects of long-term vitamin D analogue supplementation in DN and to evaluate the effectiveness of this therapy and the appropriate dosage.
... [9][10][11] Also, the results of the recent studies showed that impaired vitamin D signaling through polymorphisms of vitamin D receptor (VDR) could be involved in left ventricular hypertrophy in renal patients. [12][13][14][15][16] However, there is a lack of evidence for the effects of vitamin D supplementation on cardiometabolic biomarkers in patients with NAFLD. ...
Evidence has revealed that vitamin D status is associated with the cardiometabolic risk factors. Moreover, few gender-specific analyses have been performed in the clinical trials regarding vitamin D supplementation. As a result, assessing gender differences regarding the effects of vitamin D supplementation on some cardiometabolic biomarkers in patients with non-alcoholic fatty liver disease (NAFLD) was the aim of present study. We conducted a post hoc subgroup analysis of a double blind placebo controlled study. Patients with NAFLD randomly allocated to receive one oral pearl consisting of 50,000 IU vitamin D3 (n = 27, 13 men and 14 women) or a placebo (n = 26, 13 men and 13 women) every 14 days for four months. Serum lipid profiles, aminotransferases, high-sensitive C-reactive protein (hs-CRP), adiponectin as well as insulin resistance and dietary intakes were assessed pre- and post-study. In both genders, serum 25(OH) D3 increased significantly (P < 0.001). This increase was accompanied by significant decrease in serum total cholesterol (TC) (% of change: −7% in vitamin D vs. + 0.4% in placebo, P = 0.04) and LDL-C (%of change: −9.6% in vitamin D vs. −4% in placebo, P = 0.006) in women. However, in men, vitamin D supplementation increased the levels of serum TC (% of change: +9.2% in vitamin D vs. −10% in placebo, P = 0.02) with no significant effects on LDL-C. Moreover, vitamin D significantly reduced serum hs-CRP in women. The median daily calcium intake in both genders was well below the dietary reference intake for adults. In conclusion, improved vitamin D status might decrease serum TC and LDL-C levels as well as hs-CRP in women with NAFLD. However, it might increase serum TC in men who have low daily calcium intake. Further studies with larger sample sizes are needed to confirm these results.
... The complexity of vitamin D action is further increased by VDR gene polymorphism. The reported associations with plethora of phenotypes (including cancer, autoimmune, cardiovascular, metabolic, and renal and many other diseases) have been extensively meta-analysed and reviewed [9,10]. In general, vitamin D decreases cell proliferation and stimulates cell maturation and apoptosis. ...
Of many vitamin D extraskeletal functions, its modulatory role in insulin secretion and action is especially relevant for gestational diabetes mellitus (GDM). The aims of the present study were to determine midgestational and early postpartum vitamin D status in pregnant women with and without GDM and to describe the relationship between midgestational and postpartum vitamin D status and parallel changes of glucose tolerance. A total of 76 pregnant women (47 GDM and 29 healthy controls) were included in the study. Plasma levels of 25(OH)D were measured using an enzyme immunoassay. Vitamin D was not significantly decreased in GDM compared to controls during pregnancy; however, both groups of pregnant women exhibited high prevalence of vitamin D deficiency. Prevalence of postpartum 25(OH)D deficiency in post-GDM women remained significantly higher and their postpartum 25(OH)D levels were significantly lower compared to non-GDM counterparts. Finally, based on the oGTT repeated early postpartum persistent glucose abnormality was ascertained in 15% of post-GDM women; however, neither midgestational nor postpartum 25(OH)D levels significantly differed between subjects with GDM history and persistent postpartum glucose intolerance and those with normal glucose tolerance after delivery.
... The results reporting the effect of vitamin D on left ventricular hypertrophy are not convincing, ranging from favorable influences to negative results [106]. ...
The aim of the present paper was to review the most important mechanisms explaining the possible association of vitamin D deficiency and cardiovascular diseases, focusing on recent experimental and clinical data. Low vitamin D levels favor atherosclerosis enabling vascular inflammation, endothelial dysfunction, formation of foam cells, and proliferation of smooth muscle cells. The antihypertensive properties of vitamin D include suppression of the renin-angiotensin-aldosterone system, renoprotective effects, direct effects on endothelial cells and calcium metabolism, inhibition of growth of vascular smooth muscle cells, prevention of secondary hyperparathyroidism, and beneficial effects on cardiovascular risk factors. Vitamin D is also involved in glycemic control, lipid metabolism, insulin secretion, and sensitivity, explaining the association between vitamin D deficiency and metabolic syndrome. Vitamin D deficit was associated in some studies with the number of affected coronary arteries, postinfarction complications, inflammatory cytokines and cardiac remodeling in patients with myocardial infarction, direct electromechanical effects and inflammation in atrial fibrillation, and neuroprotective effects in stroke. In peripheral arterial disease, vitamin D status was related to the decline of the functional performance, severity, atherosclerosis and inflammatory markers, arterial stiffness, vascular calcifications, and arterial aging. Vitamin D supplementation should further consider additional factors, such as phosphates, parathormone, renin, and fibroblast growth factor 23 levels.
Background
Hypertensive disorders of pregnancy (HDP) are currently one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Recent studies provide evidence that maternal Vitamin D receptor (VDR) gene polymorphisms probably play a key role by affecting the biological function of vitamin D in some adverse pregnancy outcomes, while the relationship between the VDR gene polymorphisms and the risk of HDP remains controversial in current studies. This systematic review and meta-analysis aimed to comprehensively evaluate the association of the VDR gene polymorphisms with HDP susceptibility.
Methods
This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and a protocol has been registered in the PROSPERO (ID: CRD42022344383) before commencing this review. PubMed, Web of Science, Embase, and the Cochrane Library databases were searched until January 21, 2023. Case-control and cohort studies that reported the association of the VDR gene polymorphisms with HDP were included. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for non-randomized studies. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) of the five models (allele model, dominant model, recessive model, homozygous model, heterozygous model) were pooled respectively, and subgroup analysis was performed based on ethnicity.
Results
A total of ten studies were included. The VDR gene ApaI polymorphism was associated with HDP susceptibility in the dominant model (OR: 1.38; 95% CI [1.07–1.79]; P = 0.014) and the heterozygote model (OR: 1.48; 95% CI [1.12–1.95]; P = 0.006). In subgroup analysis, the heterozygote model (OR: 2.06; 95% CI [1.21–3.52]; P = 0.008) of the ApaI polymorphism was associated with HDP in Asians, but not in Caucasians.
Conclusion
The VDR gene ApaI polymorphism may be associated with HDP susceptibility. Insufficient evidence to support the existence of ethnic differences in this association.
The biologically most active vitamin D metabolite, 1,25-dihydroxyvitamin D3 [calcitriol or 1,25(OH)2D3] exerts the vast majority of its classical actions and attributed “non-traditional” effects by means of interaction with the vitamin D receptor (VDR). Here, we review the VDR structure and function, as well as the molecular actions of vitamin D mediated via this classical endocrine receptor. We also describe the interactions of the 1,25(OH)2D3/VDR complex with the retinoid X receptor, VDR coregulators (coactivators and corepressors) and the vitamin D-response element, whereby the expression of many 1,25(OH)2D3–responsive genes is positively or negatively controlled in many different tissues through complex conformational changes. On the other hand, chronic kidney disease (CKD) may be considered “a disease of dysfunctional receptors” since CKD has been associated with resistance to the action of many hormones including 1,25(OH)2D3. CKD and uremic toxins interfere not only with 1,25(OH)2D3 metabolism but also with various VDR processes such as basal VDR synthesis, binding and function. In view of the ubiquitous nature of VDR, several VDR activators are being developed with the aim of achieving an improved biological profile for a therapeutic application in one of the pleiotropic functions of the natural hormone, while avoiding untoward effects including excessive calcium and phosphate loading. However, randomized clinical trials are required to confirm all the proposed cardiovascular and survival benefits of the old and new VDR activators.
FokI and BsmI polymorphisms of vitamin D receptor (VDR) gene are regarded as reliable markers of disturbed vitamin D signaling pathway. Left ventricular hypertrophy (LVH) is a strong cardiovascular risk marker in end stage renal disease (ESRD) patients. Since BsmI polymorphism has been associated with LVH in ESRD patients, we addressed this study in patients with chronic kidney disease (CKD) not yet on dialysis. One hundred and forty five patients with CKD stage 3 were genotyped for FokI and BsmI VDR polymorphisms, in order to assess the relationships between these VDR polymorphisms, some markers of mineral bone disorders, and LVH measured by echocardiography. Patients bearing either the Ff heterozygous or FF homozygous genotype had significantly higher PTH values than those bearing the ff genotype. The relationships between VDR genotypes and LVH revealed a highly significant association of the BsmI Bb heterozygous genotype with LVH. In patients with CKD stage 3 BsmI B allele was independently related to LVH. Since LVH is a frequent finding in dialysis population due to several mechanisms, the presence of the same relationship in patients with CKD strengthens the hypothesis that alterations of vitamin D signaling are implicated in LVH development in patients with renal diseases.
Vitamin D, a fat-soluble prohormone, is synthesised in response to sunlight. Vitamin D requires two metabolic conversions, 25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney, to become active hormone. The active form, 1alpha,25-(OH)2D, binds to the vitamin D receptor (VDR) to modulate gene transcription and regulate mineral ion homeostasis. Vitamin D plays several roles in the body, influencing bone health as well as serum calcium and phosphate levels. Furthermore, vitamin D may modify immune function, cell proliferation, differentiation and apoptosis. Vitamin D deficiency has been associated with numerous health outcomes, including risk of rickets in children or osteomalacia in adults, increased risk of fractures, falls, cancer, autoimmune disease, infectious disease, type 1 and type 2 diabetes, hypertension and heart disease, and other diseases such as multiple sclerosis. Here, vitamin D physiology and metabolism, its genomic action and association of polymorphisms in vitamin D pathway genes with different diseases are reviewed by focusing on new findings published in the literature.
Several studies indicate a relationship between hypovitaminosis D, survival, vascular calcification and inflammation. In addition to its central role in the regulation of bone mineral metabolism, vitamin D also contributes to other systems, including the immune, cardiovascular and endocrine systems. Vitamin D analogs reduces proteinuria, in particular through suppression of the renin-angiotensin-aldosterone system (RAAS) and exerts anti-inflammatory and immunomodulatory effects. In particular vitamin D deficiency contribute to an inappropriately activated RAAS, as a mechanism for progression of chronic kidney disease (CKD) and/or cardiovascular disease. Human and sperimental models of CKD showed that vitamin D may interact with B and T lymphocytes and influence the phenotype and function of the antigen presenting cells and dendritic cells, promoting properties that favor the induction of tolerogenic T regulators rather than T effectory. Interstitial fibrosis may be prevented through vitamin D supplementation. Renal myofibroblast, an activated fibroblast with expression of a molecular hallmark α-smooth muscle actin (α-SMA), is generally considered the principal matrix-producing effector cells that are responsible for the excess production of extracellular matrix (ECM) components in the fibrotic tissues. It turns out that calcitriol effectively blocks myofibroblast activation from interstitial fibroblasts, as evidenced by suppression of TGF-β1-mediated α-SMA expression. © 2014 S. Karger AG, Basel.
Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 μg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus -4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 μg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.
We aimed to examine associations among serum 25-hydroxyvitamin D (25OHD) levels, 1,25-dihyroxyvitamin D (1,25OHD) levels, vitamin D receptor (VDR) polymorphisms, and renal function based on estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes.
In a cross-sectional study of 410 patients, chronic kidney disease (CKD) stage assessed by eGFR was compared with 25OHD, 1,25OHD, and VDR FokI (rs10735810) polymorphisms by an ordered logistic regression model adjusted for the following confounders: disease duration, calendar month, use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers or statins, and serum calcium, phosphate, and intact parathyroid hormone levels.
1,25OHD levels, rather than 25OHD levels, showed seasonal oscillations; peak levels were seen from May to October and the lowest levels were seen from December to February. These findings were evident in patients with CKD stage 3∼5 but not stage 1∼2. eGFR was in direct proportion to both 25OHD and 1,25OHD levels (P<0.0001), but it had stronger linearity with 1,25OHD (r = 0.73) than 25OHD (r = 0.22) levels. Using multivariate analysis, 1,25OHD levels (P<0.001), but not 25OHD levels, were negatively associated with CKD stage. Although FokI polymorphisms by themselves showed no significant associations with CKD stage, a significant interaction between 1,25OHD and FokITT was observed (P = 0.008). The positive association between 1,25OHD and eGFR was steeper in FokICT and CC polymorphisms (r = 0.74) than FokITT polymorphisms (r = 0.65).
These results suggest that higher 1,25OHD levels may be associated with better CKD stages in patients with type 2 diabetes and that this association was modified by FokI polymorphisms.
Background:
Left ventricular hypertrophy (LVH) is a common manifestation of cardiovascular disease and has an important prognostic value in patients with end-stage renal disease (ESRD). Vitamin D receptor (VDR) has been intensively investigated, and one of these (BsmI) already has been associated with survival in the dialysis population.
Objective:
The aim of this study was to investigate the role of VDR polymorphism (BsmI) on the development of ventricular hypertrophy and atherosclerosis in hemodialysis patients. Subject and methods. The subjects were 80 patients with end-stage renal disease on maintenance hemodialysis, and 40 healthy controls. Clinical and laboratory parameters, including genetic variation in VDR gene (BsmI), were assessed. In addition, echocardiography and intima-media thickness were performed for all subjects.
Results:
There was no significant difference in the distribution of BsmI genotypes either in patients or in the control group. The frequency of the B allele of BsmI polymorphism (41.6%) in dialysis patients was similar to that of healthy control subjects (39.2%). Patients with BB genotype had significantly lower serum concentrations of 25-hydroxy vitamin D compared to both Bb and bb genotypes. The number of B alleles was positively correlated with left ventricular mass index (LVMI), but not with intima-media thickness.
Conclusion:
These results suggest that the B alleles of the BsmI polymorphism could be considered as novel markers of altered vitamin D signaling in ESRD patients, and this alteration in BB genotype produces an increase in left ventricle mass.
For a long time, the role of vitamin D in chronic kidney disease (CKD) received less attention than treating vitamin D metabolism disorders. Low active vitamin D levels represent one of the most important factors in the pathophysiology of secondary hyperparathyroidism. For this reason, the administration of active vitamin D compounds is commenced during the course of CKD treatment. Moreover, patients with CKD exhibit a high prevalence of hypovitaminosis of 25-hydroxyvitamin D (25[OH]D) unrelated to vitamin D intake. However, several studies have recently advanced our knowledge about the effects of both the 25(OH)D and 1,25(OH)2D forms of endogenous vitamin D and the possible beneficial effects of vitamin D treatment. These studies add to the already well-known effects of vitamin D on mineral metabolism. Several studies have hypothesized a link between reduced levels of 25-OH D and a greater cardiovascular risk in the general population. Another important aspect of vitamin D metabolism is the existence of polymorphic genetic variants of the vitamin D receptors (VDRs). Most studies have aimed to determine whether VDR polymorphisms are involved in the development of secondary hyperparathyroidism (sHPT).
Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking.
To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2).
Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010.
Participants were randomly assigned to receive oral paricalcitol, 2 μg/d (n =115), or matching placebo (n = 112).
Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function.
Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.
Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease.
clinicaltrials.gov Identifier: NCT00497146.
Given that the potential role of vitamin D in cancer prevention has been widely touted, many people were surprised that cancer-related considerations didn't figure prominently in the new Dietary Reference Intakes for vitamin D established by the Institute of Medicine (IOM).(1) An IOM committee on which we served, charged with determining the population needs for vitamin D in North America, reviewed the evidence linking vitamin D with both skeletal and nonskeletal health outcomes. The committee concluded that vitamin D plays an important role in bone health and that the evidence provides a sound basis for determining the population's needs. For . . .
Several studies have shown that mineral metabolism disorders play a major role in determining a higher mortality rate for end-stage renal disease patients. Vitamin D deficiency is associated with cardiovascular events in hemodialysis patients. Recently, an association between vitamin D insufficiency and cardiovascular or renal events has been found, in patients with chronic renal failure who have not started renal replacement therapy yet. To further investigate this issue, we evaluated the relationship between blood levels of 25-hydroxyvitamin D (25-OH D; > or ≤30 ng/mL) and mortality or dialysis dependence in 104 incident consecutive patients with chronic kidney disease stages 3-5, over a period of 17 months, with a follow-up of 2 years in a cross-sectional analysis. The correlation between different levels of vitamin D and the risk of events has been estimated by using a probit model. Explanatory variables employed concerned age, sex, blood pressure, BMI, and number of co-morbid factors. The average 25-OH D concentration was of 30.13 ng/mL. During follow-up (>16 months), each patient experienced an average of 1.28 events. Vitamin D has been shown to reduce the probability of cardiovascular or renal events. Vitamin D intake for more than 12 months can reduce the probability of such events by 11.42%. Each co-morbid factor, instead, raises the probability of events by 29%. Lower probabilities of experiencing an adverse cardiovascular event might depend on higher levels of vitamin D. The influence of 25-OH D on survival in chronic kidney disease patients may be related to unrecognized factors that need to be further explored.
BACK GROUND AND OBJECTIVES: Vitamin D receptor (VDR) gene polymorphism is reported to be associated with end-stage renal disease (ESRD). We have investigated the potential role of VDR gene polymorphisms among ESRD.
The influence of VDR gene polymorphism in 258 ESRD patients comprising of 226 (87.5%) male and 32 (12.5%) females was investigated in this study. We compared ESRD patients with 569 healthy controls. The distribution of male and female among controls was 485 (85.3%) males and 84 (14.7%) females. This polymorphism was studied by using polymerase chain reaction (PCR). The product was digested by using restriction enzymes Apa1, Taq1, Fok1, and Bsm1.
We observed a significant difference in the genotype frequencies of the Apa1-aa (p = 0.0001, OR = 2.1, 95% CI = 1.45-3.08), Fok1-ff (p = 0.001, OR = 3.44, 95% CI = 1.76-6.76), and Bsm1-BB (p = 0.0004, OR = 6.8, 95% CI = 2.2-21.58). At allelic level B allele of Bsm1 was significantly different among ESRD patients as compared to controls (p = 0.0001). The combined analysis revealed that ESRD patients with Fok1 and Bsm1 polymorphism were at increased risk of 4.33-fold. The haplotype analysis revealed individuals with a/t/F/b haplotype were at greater risk of 11.0-fold (95% CI = 1.38-87.69). The serum calcium levels were significantly higher (p = 0.001) in Bsm1 "BB" genotype.
Bsm1 and Fok1 gene polymorphism of VDR gene were associated with ESRD among north Indians.
In patients undergoing dialysis, therapy with calcitriol or paricalcitol or other vitamin D agents is associated with reduced mortality. Observational data suggests that low 25-hydroxyvitamin D levels (25[OH]D) are associated with diabetes mellitus, hypertension, and cancers. However, whether low serum 25(OH)D levels are associated with mortality in the general population is unknown.
We tested the association of low 25(OH)D levels with all-cause, cancer, and cardiovascular disease (CVD) mortality in 13 331 nationally representative adults 20 years or older from the Third National Health and Nutrition Examination Survey (NHANES III) linked mortality files. Participant vitamin D levels were collected from 1988 through 1994, and individuals were passively followed for mortality through 2000.
In cross-sectional multivariate analyses, increasing age, female sex, nonwhite race/ethnicity, diabetes, current smoking, and higher body mass index were all independently associated with higher odds of 25(OH)D deficiency (lowest quartile of 25(OH)D level, <17.8 ng/mL [to convert to nanomoles per liter, multiply by 2.496]), while greater physical activity, vitamin D supplementation, and nonwinter season were inversely associated. During a median 8.7 years of follow-up, there were 1806 deaths, including 777 from CVD. In multivariate models (adjusted for baseline demographics, season, and traditional and novel CVD risk factors), compared with the highest quartile, being in the lowest quartile (25[OH]D levels <17.8 ng/mL) was associated with a 26% increased rate of all-cause mortality (mortality rate ratio, 1.26; 95% CI, 1.08-1.46) and a population attributable risk of 3.1%. The adjusted models of CVD and cancer mortality revealed a higher risk, which was not statistically significant.
The lowest quartile of 25(OH)D level (<17.8 ng/mL) is independently associated with all-cause mortality in the general population.
To study the influence of vitamin D receptor (VDR) gene polymorphism on parathyroid cell function in chronic renal failure, 85 patients who had serum PTH levels <12 pmol/L (the low intact PTH [iPTH] group) and 46 patients who had serum iPTH levels >60 pmol/L (the high iPTH group) were selected out of a total dialysis population of 170 individuals. As a result of subsequent exclusions based on several criteria in both groups (diabetic patients, serum aluminum levels, serum calcium levels, and time on dialysis), the final low iPTH group consisted of 34 patients and the final high iPTH included 32 patients. A healthy control population (n = 120) and 162 of the 170-patient dialysis population served as control groups. VDR gene polymorphism was determined by digestion with the BsmI enzyme and single-strand conformation polymorphism analysis of PCR amplified fragments. Serum iPTH levels were lower in patients with the BB genotype than in those with the Bb or bb genotype, both in the total dialysis population and when the various exclusion criteria were applied. No differences in genotypic and allelic frequencies were found between the healthy control population and the high iPTH group. However, the genotypic distribution was significantly different in the low iPTH group of patients before and after applying all exclusion criteria (P = 0.037 and P = 0.018, respectively). In the final selected population, the bb genotype was less frequent in the low iPTH group than in the total dialysis population (14.7% versus 36.4%; odds ratio, 0.3; confidence interval, 0.11 to 0.82; P = 0.01). Conversely, the BB genotype was over-represented in the low iPTH group (23.3% versus 19.7%; odds ratio, 1.9; confidence interval, 0.85 to 4.3; P = 0.1). In addition, the bb genotype and the b allele frequencies were lower in the low iPTH group than in the high iPTH group (14.7% versus 34.4%, P = 0.06, and 41.2% versus 60.9%, P = 0.02, respectively), and the BB genotype and the B allele were significantly more frequent in the low PTH group than in the high iPTH group (32.3% versus 12.5%, P = 0.05, and 58.8% versus 39.1%, P = 0.02, respectively). Thus, VDR gene polymorphism influences parathyroid function in chronic renal failure.
The actions of 1,25(OH)2D3-VDR that have emerged from recent studies include, but clearly transcend, the bone and calcium/phosphate homeostasis effects originally attributed to vitamin D. This new understanding now encompasses many of the tissues formerly reported to contain vitamin D receptors, but for which no function of the vitamin-derived hormone could be ascribed. The insights gained from VDR knockout and allelic variation research confirm and extend these concepts, raising the prospect that, for the purpose of preventive measures, assessment of VDR polymorphisms may ultimately become part of a strategy to better identify and treat persons at risk for common disorders such as osteoporosis, breast cancer, or prostate cancer. We have learned much about VDR structure/function from natural mutations in 1,25-(OH)2D3-resistant patients and from site-directed mutagenesis experiments, as well as gained insight from the elucidation of analogous crystal structures for RAR, RXR, and TR. The next few years will no doubt witness a growing structural understanding of VDR, presumably culminating in the crystallographic resolution of physical details of liganded versus unliganded forms of VDR, perhaps in the absence and presence of various protein partners and/or VDRE binding sites. Such structural information should allow for the design of the next generation of synthetic analogs possessing the potential capability of selectivity controlling individual 1,25(OH)2D3 responses within the organism. Fundamental investigations also have led to an enhanced appreciation of the sequence of events in nuclear VDR signal transduction, offering promise that we may be able to understand how diverse 1,25(OH)2D3 agonists could differentially manipulate these steps in a promoter and/or tissue-specific fashion. Such analogs would therefore be endowed with therapeutic potential not only for classic VDR actions in calcium/phosphate homeostasis and bone mineralization, but also for hyperproliferative skin disorders and various types of cancer. A novel type of analog that will be useful in studies of VDR action is an authentic receptor antagonist, and preliminary reports((200,201)) indicate that this reagent may be available soon. Another new frontier of VDR function at the molecular level is clearly that of characterizing VDR-interacting proteins, and identifying how they mediate 1,25(OH)2D3 signaling within the context of specific gene promoters. These biochemical and genetic investigations may reveal mechanisms for potential interactions of 1,25(OH)2D3 with signaling pathways for other hormones, growth factors, and cytokines that physiologically modulate the wide array of vitamin D bioeffects.
Since bone mineral density may be influenced by the polymorphisms of the vitamin D receptor (VDR) gene, we studied whether VDR genotypes might drive the progression toward hyperparathyroidism or hypoparathyroidism in patients with end-stage renal disease. On the basis of their parathyroid hormone (PTH) levels, we divided 99 patients undergoing dialysis into 2 groups: 56 patients with hypoparathyroidism (PTH < 104 pg/mL [< 11 pmol/L]) and 43 with hyperparathyroidism (PTH > 261 pg/mL [> 27.5 pmol/L]). The BB polymorphism was more frequent in patients with hypoparathyroidism (34%) than in patients with hyperparathyroidism (16%), but the difference did not reach statistical significance. Patients with the B allele and BB genotype had a significantly lower dialytic age and serum PTH and alkaline phosphatase levels than patients with the b allele and bb genotype. These results suggest that in end-stage renal disease, the BB genotype may mark a higher risk of developing hypoparathyroidism and diminished bone turnover.
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
Bsml vitamin D receptor (VDR) gene polymorphism has been reported to influence the progression of secondary hyperparathyroidism but it is not known how much the genetic background contributes to the need for parathyroidectomy (PTx). We investigated the influence of VDR gene polymorphism on PTx in patients with different dialysis vintage.
We studied 121 parathyroidectomized HD patients ("PTx " group). Patients who had required early parathyroidectomy ("early PTx" group) or late parathyroidectomy ("late PTx" group) were analyzed separately. The cut-off point between these two groups was 89 months (mean time on hemodialysis (HD) before parathyroidectomy). Serum intact parathyroid hormone, calcium, phosphorus and alkaline phosphatase were measured. Bsml genotypes were analyzed by polymerase chain reaction. Statistical analysis was done with univariant analysis of variance (ANOVA) to compare the genotype groups and general factorial ANOVA, entering time on HD as the dependent variable, with genotype, sex, age and chronic renal failure (CRF) etiology as factors. As a control group for the association studies we determined genotypic frequencies in 162 HD patients ("total HD" group), and in a healthy control population of 120 individuals ("healthy" group), tested by contingency table analysis and the chi-square test.
No significant differences were found between the genotypes except for the time on HD. General factorial ANOVA showed that the adjusted means of the time on HD were significantly different for the various genotypes (p = 0.015). The BB genotype was significantly less frequent in the "early PTx " group than in the "total HD" and "late PTx" groups.
Individuals with the BB genotype can remain longer on HD before they need parathyroidectomy.
The vitamin D endocrine system is involved in a wide variety of biological processes including bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation. Variations in this endocrine system have, thus, been linked to several common diseases, including osteoarthritis (OA), diabetes, cancer, cardiovascular disease, and tuberculosis. Evidence to support this pleiotropic character of vitamin D has included epidemiological studies on circulating vitamin D hormone levels, but also genetic epidemiological studies. Genetic studies provide excellent opportunities to link molecular insights with epidemiological data and have therefore gained much interest. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have modest and subtle but true biological effects. Their abundance in the human genome as well as their high frequencies in the human population have made them targets to explain variation in risk of common diseases. Recent studies have indicated many polymorphisms to exist in the vitamin D receptor (VDR) gene, but the influence of VDR gene polymorphisms on VDR protein function and signaling is largely unknown. So far, three adjacent restriction fragment length polymorphisms for BsmI, ApaI, and TaqI, respectively, at the 3' end of the VDR gene have been the most frequently studied. Because these polymorphisms are probably nonfunctional, linkage disequilibrium with one or more truly functional polymorphisms elsewhere in the VDR gene is assumed to explain the associations observed. Research is therefore focussed on documenting additional polymorphisms across the VDR gene to verify this hypothesis and on trying to understand the functional consequences of the variations. Substantial progress has been made that will deepen our understanding of variability in the vitamin D endocrine system and might find applications in risk assessment of disease and in predicting response-to-treatment.
Patients with ESRD commonly experience secondary hyperparathyroidism, a condition primarily managed with activated injectable vitamin D. The biologic effects of vitamin D, however, are widespread, and it is possible that activated injectable vitamin D alters survival in ESRD. This hypothesis was tested in a historical cohort study of incident hemodialysis patients who lived throughout the United States between January 1996 and December 1999. The primary outcome was 2-yr survival among those who survived for at least 90 d after initiation of chronic hemodialysis. During this period, 51,037 chronic hemodialysis patients survived for at least 90 d from the initiation of hemodialysis, and in the ensuing 2 yr, 37,173 received activated injectable vitamin D and 13,864 did not. At 2 yr, mortality rates were 13.8/100 person-years in the group that received injectable vitamin D compared with 28.6/100 person-years in the group that did not (P < 0.001). Cox proportional hazards analyses adjusting for several potential confounders and examining injectable vitamin D therapy as a time-dependent exposure suggested that compared with patients who did not receive injectable vitamin D, the 2-yr survival advantage associated with the group that did receive injectable vitamin D was 20% (hazard ratio, 0.80; 95% confidence interval, 0.76 to 0.83). The incidence of cardiovascular-related mortality was 7.6/100 person-years in the injectable vitamin D group, compared with 14.6/100 person-years in the non-vitamin D group (P < 0.001). The benefit of injectable vitamin D was evident in 48 of 49 strata examined, including those with low serum levels of intact parathyroid hormone and elevated levels of serum calcium and phosphorus, situations in which injectable vitamin D is often withheld. Repeating the entire analysis using marginal structural models to adjust for time-dependent confounding by indication yielded a survival advantage of 26% (hazard ratio, 0.74; 95% confidence interval, 0.71 to 0.79) associated with the injectable vitamin D group. In this historical cohort study, chronic hemodialysis patients in the group that received injectable vitamin D had a significant survival advantage over patients who did not. Randomized clinical trials would permit definitive conclusions.
We investigated the relationship between vitamin D receptor (VDR) start codon polymorphism and serum levels of PTH, calcidiol, and calcium in 64 Spanish patients with chronic renal failure (CRF). An exon 2 fragment of the VDR gene was amplified by PCR, and cleaved with the restriction enzyme FokI. The alleles were identified according to the digestion pattern obtained as F (absence of restriction site) and f (presence of restriction site). Genotype frequencies in the patient population were 54.7% FF, 28.1% Ff and 17.2% ff, vs 46.7% FF, 43.3% Ff and 10% ff in a healthy control population. The difference between the two populations was statistically significant (p<0.01). Within the patient population, mean serum PTH level in the FF group was significantly higher (159.77+/-25.69 pg/ml) than in both the Ff and ff groups (106.67+/-19.07 and 77.55+/-15.85 pg/ml, respectively; p<0.05). However there were no significant differences in serum levels of calcidiol or calcium among genotypes. These results suggest that FokI polymorphisms of the VDR gene may determine parathyroid response in CRF patients.
The vitamin D endocrine system is central to the control of bone and calcium homeostasis. Thus, alterations in the vitamin D pathway lead to disturbances in mineral metabolism. Furthermore, a role for vitamin D has been suggested in other diseases, like cancer, diabetes and cardiovascular disease. Expression and nuclear activation of the vitamin D receptor (VDR) are necessary for the effects of vitamin D. Several genetic variations have been identified in the VDR. DNA sequence variations, which occur frequently in the population, are referred to as "polymorphisms" and can have biological effects. To test whether there is a linkage between VDR polymorphisms and diseases, epidemiological studies are performed. In these studies, the presence of a variation of the gene is studied in a population of patients, and then compared to a control group. Thus, association studies are performed, and a link among gene polymorphisms and diseases can be established. Since the discovery of VDR polymorphisms a number of papers have been published studying its role in bone biology, renal diseases, diabetes, etc. The purpose of this review is to summarize the vast amount of information regarding vitamin D receptor polymorphisms and human diseases, and discuss its possible role as diagnostic tools.
Results of several epidemiologic and clinical studies have suggested that there is an excess risk of hypertension and diabetes mellitus in persons with suboptimal intake of vitamin D.
We examined the association between serum levels of 25-hydroxyvitamin D (25[OH]D) and select cardiovascular disease risk factors in US adults. A secondary analysis was performed with data from the Third National Health and Nutrition Examination Survey, a national probability survey conducted by the National Center for Health Statistics between January 1, 1988, and December 31, 1994, with oversampling of persons 60 years and older, non-Hispanic black individuals, and Mexican American individuals.
There were 7186 male and 7902 female adults 20 years and older with available data in the Third National Health and Nutrition Examination Survey. The mean 25(OH)D level in the overall sample was 30 ng/mL (75 nmol/L). The 25(OH)D levels were lower in women, elderly persons (>or=60 years), racial/ethnic minorities, and participants with obesity, hypertension, and diabetes mellitus. The adjusted prevalence of hypertension (odds ratio [OR], 1.30), diabetes mellitus (OR, 1.98), obesity (OR, 2.29), and high serum triglyceride levels (OR, 1.47) was significantly higher in the first than in the fourth quartile of serum 25(OH)D levels (P<.001 for all).
Serum 25(OH)D levels are associated with important cardiovascular disease risk factors in US adults. Prospective studies to assess a direct benefit of cholecalciferol (vitamin D) supplementation on cardiovascular disease risk factors are warranted.
OBJECTIVE
To test the hypothesis that vitamin D receptor polymorphism is associated with calcific aortic valve stenosis.
DESIGN
The distribution of one polymorphism of the vitamin D receptor (BsmI B/b) was examined in 100 consecutive patients with calcific valvar aortic stenosis and compared with a control group of 100 patients (paired match for age, sex, and the presence of coronary artery disease from a total of 630 patients without calcified aortic valves). Polymerase chain reaction and restriction fragment length polymorphism were used to determine genotypes.
RESULTS
There was a significant difference in vitamin D receptor allele and genotype frequencies between the two groups. The allele B had a higher prevalence in patients with calcific aortic stenosis (B = 0.56, b = 0.44) than in the control cohort (B = 0.40, b = 0.60) (p = 0.001).
CONCLUSIONS
There is a significant association of vitamin D receptor polymorphism with calcific aortic valve stenosis. The B allele of the vitamin D receptor is more common in patients with calcific aortic valve stenosis. It now needs to be evaluated whether other genes that control calcium homeostasis are involved in the pathogenesis of this disorder.
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor–null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] synthesis also led to an increase in renin expression, whereas 1,25(OH)2D3 injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)2D3 markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
We investigated the relationship between BsmI/ApaI polymorphisms in vitamin D receptor gene and diabetic nephropathy in a Han Chinese population. PCR-restriction fragment length polymorphism was used to test the genotype and allele frequency of BsmI and ApaI polymorphisms in 304 patients with type 2 diabetes mellitus (DM group) and 100 control individuals (ND group). The DM group was further divided into DN0 (no diabetic nephropathy), DN1 (diabetes with small amount of albuminuria), DN2 (diabetes with large amount of albuminuria), L/NDN (late-onset DN after 5 years/no DN over the whole follow-up period of 5 years) and EDN (early-onset diabetic nephropathy occurring within first year) subgroup. We found that (1) genotype and allele frequency of BsmI polymorphism had significant difference between DM and ND group; BB+Bb genotype and B allele frequency were significantly higher in DN2 group than in ND and DN0 group; the ApaI polymorphism and allele frequency did not show any difference between DM and ND group; (2) BsmI BB+Bb genotype and B allele frequency were significantly higher in EDN group than in L/NDN group; (3) among patients with nephropathy, albumin excretion rate (AER) in 24-hour urine was significantly higher in those with BB+Bb phenotype than in those with bb phenotype (P<0.01), (4) unconditional logistic regression analysis showed that BsmI BB+Bb genotype was not only correlated with type 2 diabetic nephropathy, but also correlated with early-onset type 2 diabetic nephropathy. We conclude that the allele B (BB or Bb genotype) in vitamin D receptor gene is correlated with large amount albuminuria in the Han Chinese population with type 2 diabetes, and is probably a risk factor for early-onset diabetic nephropathy.
Angiotensin-converting enzyme (ACE) inhibitors ameliorate the progression of renal disease. In combination with vitamin D receptor activators, they provide additional benefits. In the present study, uremic (U) rats were treated as follows: U+vehicle (UC), U+enalapril (UE; 25 mg/l in drinking water), U+paricalcitol (UP; 0.8 μg/kg ip, 3 × wk), or U+enalapril+paricalcitol (UEP). Despite hypertension in UP rats, proteinuria decreased by 32% vs. UC rats. Enalapril alone, or in combination with paricalcitol, further decreased proteinuria (≈70%). Glomerulosclerosis and interstitial infiltration increased in UC rats. Paricalcitol and enalapril inhibited this. The increase in cardiac atrial natriuretic peptide (ANP) seen in UC rats was significantly decreased by paricalcitol. Enalapril produced a more dramatic reduction in ANP. Renal oxidative stress plays a critical role in inflammation and progression of sclerosis. The marked increase in p22(phox), a subunit of NADPH oxidase, and decrease in endothelial nitric oxide synthase were inhibited in all treated groups. Cotreatment with both compounds inhibited the uremia-induced increase in proinflammatory inducible nitric oxide synthase (iNOS) and glutathione peroxidase activity better than either compound alone. Glutathione reductase was also increased in UE and UP rats vs. UC. Kidney 4-hydroxynonenal was significantly increased in the UC group compared with the normal group. Combined treatment with both compounds significantly blunted this increase, P < 0.05, while either compound alone had no effect. Additionally, the expression of Mn-SOD was increased and CuZn-SOD decreased by uremia. This was ameliorated in all treatment groups. Cotreatment with enalapril and paricalcitol had an additive effect in increasing CuZn-SOD expression. In conclusion, like enalapril, paricalcitol alone can improve proteinuria, glomerulosclerosis, and interstitial infiltration and reduce renal oxidative stress. The effects of paricalcitol may be amplified when an ACE inhibitor is added since cotreatment with both compounds seems to have an additive effect on ameliorating uremia-induced changes in iNOS and CuZn-SOD expression, peroxidase activity, and renal histomorphometry.
Despite treatment with renin–angiotensin–aldosterone system (RAAS) inhibitors, patients with diabetes have increased risk of progressive renal failure that correlates with albuminuria. We aimed to assess whether paricalcitol could be used to reduce albuminuria in patients with diabetic nephropathy.
In this multinational, placebo-controlled, double-blind trial, we enrolled patients with type 2 diabetes and albuminuria who were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Patients were assigned (1:1:1) by computer-generated randomisation sequence to receive 24 weeks’ treatment with placebo,1 μg/day paricalcitol, or 2 μg/day paricalcitol. The primary endpoint was the percentage change in geometric mean urinary albumin-to-creatinine ratio (UACR) from baseline to last measurement during treatment for the combined paricalcitol groups versus the placebo group. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00421733.
Between February, 2007, and October, 2008, 281 patients were enrolled and assigned to receive placebo(n=93), 1 μg paricalcitol (n=93), or 2 μg paricalcitol (n=95); 88 patients on placebo, 92 on 1 μg paricalcitol, and 92 on2 μg paricalcitol received at least one dose of study drug, and had UACR data at baseline and at least one timepoint during treatment, and so were included in the primary analysis. Change in UACR was: –3% (from 61 to 60 mg/mmol;95% CI –16 to 13) in the placebo group; –16% (from 62 to 51 mg/mmol; –24 to –9) in the combined paricalcitol groups, with a between-group difference versus placebo of –15% (95% CI –28 to 1; p=0.071); –14% (from 63 to 54 mg/mmol; –24 to –1) in the 1 μg paricalcitol group, with a between-group difference versus placebo of –11%(95% CI –27 to 8; p=0.23); and –20% (from 61 to 49 mg/mmol; –30 to –8) in the 2 μg paricalcitol group, with a between-group difference versus placebo of –18% (95% CI –32 to 0; p=0.053). Patients on 2 μg paricalcitol showed a nearly, sustained reduction in UACR, ranging from –18% to –28% (p=0.014 vs placebo). Incidence of hypercalcaemia,adverse events, and serious adverse events was similar between groups receiving paricalcitol versus placebo.
Addition of 2 μg/day paricalcitol to RAAS inhibition safely lowers residual albuminuria in patients with diabetic nephropathy, and could be a novel approach to lower residual renal risk in diabetes.
Abbott.
Left ventricular hypertrophy (LVH) is a strong cardiovascular risk marker in end-stage renal disease (ESRD) patients. Vitamin D deficiency and/or disturbed vitamin D signaling has been implicated in LVH in experimental models. Because the BsmI vitamin D receptor VDR gene polymorphism may alter VDR function, we performed a cross-sectional and longitudinal study in a cohort of 182 dialysis patients to investigate (1) the relationship between BsmI VDR gene polymorphism and left ventricular mass index (LVMI) measured by echocardiography and (2) the predictive power of this polymorphism for progression in LVH over a 18 +/- 2 months of follow-up. As a reference group, we used 175 healthy subjects matched to the study population as for age and sex. The distribution of BsmI genotypes did not significantly deviate from Hardy-Weinberg equilibrium either in patients or in the control group of healthy subjects. The frequency of the B allele of BsmI polymorphism (40.4%) in dialysis patients was similar to that of healthy control subjects (38.6%), and the number of B alleles was directly related to LVMI (r = 0.20, P = .007). This relationship remained robust (beta = 0.19, P = .006) in multivariate analysis adjusting for traditional and nontraditional risk factors and antihypertensive and calcitriol treatment. In the longitudinal study, LVMI rose from 60.1 +/- 17.9 to 64.2 +/- 19.3 g/m(2.7) (P < .001), and again, the number of B alleles was associated with LVMI changes both in crude and in fully adjusted analyses. These cross-sectional and longitudinal observations coherently support the hypothesis that altered vitamin D signaling is implicated in LVH in ESRD patients.
Specific receptors for 1,25-dihydroxyvitamin D3, the active hormonal form of vitamin D3, were demonstrated in low salt chromatin preparations from normal rat hearts. Sucrose gradient analysis of KCl-extracted chromatin yielded a significant (P less than 0.005) peak of specific [3H]1,25-dihydroxyvitamin D3 binding in the 3.6S region. The peak of [3H]1,25-dihydroxyvitamin D3 binding was abolished by excess 1,25-dihydroxyvitamin D3, but not by 50 nM 25-hydroxyvitamin D3 nor by 1.0 microM levels of estradiol-17B, cortisol, or promegestone, demonstrating steroid specificity characteristic for such receptors. Upon Scatchard analysis this putative cardiac 1,25-dihydroxyvitamin D3 receptor yielded a single binding component with high affinity (KD = 0.36 nM) and low capacity (Nmax = 33 fmol/g tissue). Coupled with evidence for the presence of calcium binding proteins in this tissue, these observations suggest functional roles for 1,25-dihydroxyvitamin D3 and its receptors in cardiac muscle, possibly in regulating intracellular effects of calcium.
Circulating levels of the calcium-regulating hormones, calcitonin, calcitriol, and parathyroid hormone, were analyzed in relation to plasma renin activity in 10 persons with normal blood pressure and in 51 persons with essential hypertension. Calcitriol (p less than 0.008) and parathyroid hormone (p less than 0.01) levels were elevated in hypertensives with low renin activity, whereas calcitonin levels were higher in patients with high renin activity (p less than 0.008), compared with normotensive controls and other hypertensive patients. Continuous relationships were observed between calcitriol levels and plasma renin activity in all patients (r = -0.65, p less than 0.001) and between parathyroid hormone levels and urinary sodium excretion in hypertensive patients with low renin activity (r = -0.63, p less than 0.01). Together, these results support a linkage between calcium metabolism and renin-sodium factors in essential hypertension. Calcium-regulating hormones and the renin-aldosterone system may coordinately mediate the blood pressure effects of differing dietary calcium and sodium intakes at the cellular level by altering cellular handling of monovalent and divalent ions.
Adynamic bone disease unrelated to aluminum deposition, with low parathyroid hormone (PTH) levels, has increased in patients with end-stage renal failure. Some patients present with severe secondary hyperparathyroidism despite calcitriol administration and phosphate restriction. Because therapeutic and environmental factors are now similar among hemodialyzed patients, the variable incidence of secondary hyperparathyroidism may be caused by genetic heterogeneity. To examine this possibility, we analyzed restriction fragment length polymorphisms of the vitamin D receptor (VDR) gene in 877 Japanese hemodialysis patients. VDR allelic polymorphism was determined by the method of Morrison et al. Polymerase chain reaction (PCR) amplification and a BsmI endonuclease restriction site at the 5' end of the VDR gene defined BB (absence of restriction site on both alleles), Bb (heterozygous), or bb (restriction site on both alleles). The mean serum PTH level was lower in BB patients (86 +/- 102 pg/mL) than in bb patients (148 +/- 217 pg/mL; P < 0.05). The serum osteocalcin level was also lower in BB than in bb patients (P < 0.05). If results were re-analyzed excluding patients with a history of dialysis exceeding 10 years or those with non-insulin-dependent diabetes mellitus (NIDDM) or who had undergone parathyroidectomy, the differences in serum PTH levels were greater. However, there was no significant difference in serum PTH levels among the VDR genotypes, only for patients with NIDDM. The present study shows that patients with the b allele for the VDR gene have more severe secondary hyperparathyroidism than patients without the b allele. However, NIDDM or a long history of hemodialysis has a stronger power to influence PTH secretion.
To evaluate the response of circulating intact parathyroid hormone (iPTH) on myocardial hypertrophy in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), echocardiographic and neurohormonal assessments were performed over a 15-week period in 15 HD patients with SHPT before and after calcitriol treatment and 10 HD control patients with SHPT not receiving calcitriol therapy. We prospectively studied a group of 15 patients with significantly elevated iPTH levels (iPTH >450 pg/mL) receiving calcitriol (2 microg after dialysis twice weekly). Clinical assessment, medication status, and biochemical and hematological measurements were performed once a month. Throughout the study, calcium carbonate levels were modified to maintain serum phosphate levels at less than 6 mg/dL, but body weight, antihypertensive medication, and ultrafiltration dose remained constant. In patients treated with calcitriol, an adequate reduction of iPTH levels was found (1,112 +/- 694 v 741 +/- 644 pg/mL; P < 0.05) without changes in values of serum ionized calcium (iCa++), phosphate, or hematocrit. Blood pressure (BP), cardiac output (CO), and total peripheral resistance (TPR) did not significantly change. After 15 weeks of treatment with calcitriol, M-mode echocardiograms showed pronounced reductions in interventricular wall thickness (13.9 +/- 3.6 v 12.8 +/- 3.10 mm; P = 0.01), left ventricular posterior wall thickness (12.5 +/- 2.4 v 11.3 +/- 1.8 mm; P < 0.05), and left ventricle mass index (LVMi; 178 +/- 73 v 155 +/- 61 g/m2; P < 0.01). However, in control patients, these changes were not found after the treatment period. In addition, sequential measurements of neurohormonal mediator levels in patients receiving calcitriol showed that plasma renin (18.5 +/- 12.7 v 12.3 +/- 11.0 pg/mL; P = 0.007), angiotensin II (AT II; 79.7 +/- 48.6 v 47.2 +/- 45.7 pg/mL; P = 0.001), and atrial natriuretic peptide (ANP; 16.6 +/- 9.7 v 12.2 +/- 4.4 pg/mL; P = 0.03) levels significantly decreased, whereas antidiuretic hormone (ADH), epinephrine, and norepinephrine levels did not change significantly. The percent change in LVMi associated with calcitriol therapy had a strong correlation with the percent change in iPTH (r = 0.52; P < 0.05) and AT II (r = 0.47; P < 0.05) levels. We conclude that the partial correction of SHPT with intravenous calcitriol causes a regression in myocardial hypertrophy without biochemical or hemodynamic changes, such as heart rate, BP, and TPR. The changes in plasma levels of iPTH and, secondarily, plasma levels of neurohormones (especially AT II) after calcitriol therapy may have a key role in attenuating ventricular hypertrophy in SHPT.
BsmI vitamin D receptor (VDR) gene polymorphism has been associated with the severity of hyperparathyroidism in patients on hemodialysis. The aim of this study was to analyze the influence of this polymorphism on parathyroid function and serum calcitriol levels in patients with different degrees of chronic renal failure (CRF) before dialysis.
A total of 248 CRF patients, divided into three groups according to creatinine clearance (CCr; mild CRF group> 60 to </=85 ml/min, N = 54; moderate CRF group> 35 to </=60 ml/min, N = 113; severe CRF group> 10 to </=35 ml/min, N = 81), had their serum intact parathyroid hormone (iPTH) and calcitriol levels measured and BsmI genotype frequencies estimated by polymerase chain reaction (PCR) analysis. Diabetics, those on treatment with steroids, vitamin D or derivatives, and phosphorus binding agents were excluded. All those with serum calcium levels of <2.25 mmol/liter or> 2.5 mmol/liter and serum phosphorus levels of> 1.6 mmol/liter or who needed phosphorus binding agents were excluded. The statistical analysis was done with the general factorial analysis of variance entering first PTH and then calcitriol as the dependent variable; the genotype (BB, Bb and bb), sex and CCr group were defined as factors; and covariables included serum calcium, serum phosphorus, 1/creatinine versus time slope, PTH when calcitriol was the dependent variable, and calcitriol when PTH was the dependent variable.
When serum PTH levels were entered as the dependent variable, serum calcium, CCr group, and the interaction of genotype with the CCr group were found to be significant factors (P = 0.025, P <0.001 and P = 0.039, respectively). When serum calcitriol levels were entered as the dependent variable, genotype, the interaction of genotype with CCr, the CCr group, and the 1/creatine versus time slope were found to be significant (P = 0.027, P = 0.028, P <0.001 and P = 0.044, respectively). The marginal means of PTH, adjusted with the general factorial analysis of variance across the three groups were: (a) mild CRF group, BB 5.3 pmol/liter (CI 0 to 13.8), Bb 5.5 pmol/liter (CI 2 to 9), bb 5.4 pmol/liter (CI 0.6 to 10.2); (b) moderate CRF group, BB 6.2 pmol/liter (CI 1.5 to 10.9), Bb 7.8 pmol/liter (CI 5.3 to 10.3), bb 7.5 pmol/liter (CI 4.8 to 10.1); (c) severe CRF group, BB 9.3 pmol/liter (CI 4.2 to 14.3), Bb 17.1 pmol/liter (CI 13.9 to 20.2), bb 21.9 pmol/liter (CI 18.7 to 25.2). The marginal means of calcitriol adjusted with the general factorial analysis of variance across the three groups were: (a) mild CRF group, BB 47 pg/ml (CI 37 to 57), Bb 40.9 pg/ml (CI 37 to 44.8), bb 32.6 pg/ml (CI 26.8 to 38. 4); (b) moderate CRF group, BB 24.1 pg/ml (CI 18.3 to 29.8), Bb 26.6 pg/ml (CI 23.5 to 29.7), bb 25.3 pg/ml (CI 22 to 28.6); (c) severe CRF group, BB 27.4 pg/ml (CI 21.3 to 33.5), Bb 19.4 pg/ml (CI 15.5 to 23.2), bb 20.4 pg/ml (CI 16.1 to 24.7).
The progression of hyperparathyroidism is slower in predialysis patients with BB genotypes than in the other genotypes. Also, calcitriol levels are less reduced in the BB genotype, which may act to lessen the severity of secondary hyperparathyroidism.
To test the hypothesis that vitamin D receptor polymorphism is associated with calcific aortic valve stenosis.
The distribution of one polymorphism of the vitamin D receptor (BsmI B/b) was examined in 100 consecutive patients with calcific valvar aortic stenosis and compared with a control group of 100 patients (paired match for age, sex, and the presence of coronary artery disease from a total of 630 patients without calcified aortic valves). Polymerase chain reaction and restriction fragment length polymorphism were used to determine genotypes.
There was a significant difference in vitamin D receptor allele and genotype frequencies between the two groups. The allele B had a higher prevalence in patients with calcific aortic stenosis (B = 0.56, b = 0.44) than in the control cohort (B = 0.40, b = 0.60) (p = 0.001).
There is a significant association of vitamin D receptor polymorphism with calcific aortic valve stenosis. The B allele of the vitamin D receptor is more common in patients with calcific aortic valve stenosis. It now needs to be evaluated whether other genes that control calcium homeostasis are involved in the pathogenesis of this disorder.
BsmI polymorphism of the vitamin D receptor gene has been linked to hyperparathyroidism severity and calcitriol levels. The aim of this study was to analyze the response to a single bolus of calcitriol in hemodialysis patients with the BB and bb genotype.
Twenty homozygous BsmI hemodialysis patients (9 BB and 11 bb).
Hyperparathyroidism was assessed comparing basal PTH levels, and in 17 patients, also measuring the inhibition with hypercalcemia. Patients were given a bolus of calcitriol and PTH in absolute terms and in percentages relative to the baseline values at 24, 48 and 72 hours after the bolus were measured. All biochemical parameters were compared between genotypes with univariant ANOVA and additionally, PTH relative values were compared with general factorial analysis of variance, adjusting for calcium and phosphorus. Means were also compared within each genotype between consecutive determinations with non-parametric Wilcoxon analysis, using each patient as his/her own control. The response to calcitriol was also assessed by the area under the curve for each patient and was subsequently compared between genotypes.
There were no differences on hyperparathyroidism severity between the groups. The BB genotype showed a better response than bb to calcitriol 72 hours after the bolus (percentage relative to basal PTH value: BB: 63%, bb: 88.6%, p = 0.03; BB vs bb with univariant ANOVA). When general factorial analysis of variance was applied, adjusting for serum calcium and phosphorus, genotype showed a significant influence on the response to calcitriol at 72 hours (p = 0.04). When each patient was used as his/her own control, the BB genotype showed a significant decrease in PTH levels at 48 and 72 hours (p = 0.00 baseline vs 48 h, and p = 0.01 baseline vs 72h) whereas the bb did not.
BsmI polymorphism of the VDR gene induces differences on the response to a single bolus of calcitriol independently of calcium and phosphorus.
The BsmI polymorphism of the vitamin D receptor (VDR) gene influences mineral metabolism and the course of cancers and infections. The poly-A polymorphism is in linkage disequilibrium with BsmI and could be responsible for clinical associations attributed to BsmI. The objective of this work is to study the influence of VDR polymorphisms on survival of 143 prevalent hemodialysis (HD) patients followed up for 4 years. Chi-square test was used to study the association between survival and these polymorphisms. Cox analysis was performed, adjusting for comorbid conditions in the entire HD population, groups of patients on HD therapy for less than 5 and 3 years before entering 4 years of observation, patients without diabetes, and patients treated with calcitriol. Survival was analyzed by means of Kaplan-Meier according to BsmI genotypes. Results showed a strong influence of the BsmI polymorphism on survival. The bb genotype was overrepresented among survivors (45.7%) compared with nonsurvivors (21.6%), and Cox analysis showed a significant influence of age, diabetes, calcitriol treatment, and BsmI polymorphism in all groups (in the entire population, Exp(B): BB, 3.9; and Bb, 3 with respect to bb), and also of phosphorus in patients without diabetes and calcitriol-treated patients. Survival means by Kaplan-Meier were as follows: BB, 983 days; Bb, 1,152 days; and bb, 1,290 days (log-rank P = 0.01). The BsmI polymorphism influences survival in HD patients, whereas the poly-A and FokI polymorphisms do not.
Left ventricular hypertrophy (LVH) is exceedingly frequent in patients undergoing dialysis. Cardiac mass is proportional to body size, but the influence of various indexing methods has not been studied in patients with end-stage renal disease. The issue is important because malnutrition and volume expansion would both tend to distort the estimate of LV mass (LVM) in these patients. In a cohort of 254 patients, the prognostic impact on all-cause mortality and cardiovascular outcomes of LVH values, calculated according to two established methods of indexing, either body surface area (BSA) or height(2.7), was assessed prospectively. When LVM was analyzed as a categorical variable, the height(2.7)-based method identified a larger number of patients with LVH than the corresponding BSA-based method. One hundred and thirty-seven fatal and nonfatal cardiovascular events occurred during the follow-up period. Overall, 90 patients died, 51 of cardiovascular causes. In separate Cox models, both the LVM/height(2.7) and the LVM/BSA index independently predicted total and cardiovascular mortality (P < 0.001). However, the height(2.7)-based method coherently produced a closer-fitting model (P < or = 0.02) than did the BSA-based method. The height(2.7) index was also important for the subcategorization of patients according to the presence of concentric or eccentric LVH because the prognostic value of such subcategorization was apparent only when the height(2.7)-based criterion was applied. In conclusion, LVM is a strong and independent predictor of survival and cardiovascular events in patients undergoing dialysis. The indexing of LVM by height(2.7) provides more powerful prediction of mortality and cardiovascular outcomes than the BSA-based method, and the use of this index appears to be appropriate in patients undergoing dialysis.
Both in vitro and in vivo studies have shown that calcitriol, the active form of vitamin D, is involved in hematopoiesis. We hypothesized that the vitamin D receptor (VDR) genotype, which may differentiate response to endogenous or exogenous active vitamin D, has a role in the management of anemia in hemodialysis (HD) patients.
The VDR BsmI gene polymorphism was determined in 91 HD patients and 85 healthy controls. In addition to well-known factors responsible for both anemia and inadequate response to erythropoietin (EPO), we examined the contribution of the VDR genotype to hematocrit (Hct), hemoglobin (Hb) level, total weekly dose of EPO, and EPO-Hb ratio as an index of patient EPO need.
Genotype distributions for the VDR gene were under the Hardy-Weinberg equilibrium and similar in patients and controls (genotypes BB, Bb, and bb: 22.0%, 38.5%, and 39.5% in patients versus 24.7%, 48.2%, and 27.1% in controls). There were statistically significant differences in Hct, Hb level, EPO dose, and EPO-Hb ratio in patients with the three BsmI genotypes, whereas the other parameters were the same. Comparison of patients with an Hb level less than versus greater than 11 g/dL showed that the former patients had lower albumin levels (P = 0.001), higher C-reactive protein levels (P = 0.014), and a greater frequency of BB genotype (P < 0.001). Similarly, comparison of patients with an EPO-Hb ratio in the highest quartile versus those in the lowest quartile showed that the former patients had lower albumin and transferrin levels (P = 0.013 for both) and greater frequencies of BB genotype (P = 0.016). In logistic regression analysis, both BB genotype and low serum albumin level were found to be the only independent predictors for an Hb level less than 11 g/dL (P < 0.001 and P = 0.046, respectively). Both parameters also predicted being in the highest quartile of EPO-Hb ratio (P = 0.004 for both).
The VDR BsmI gene polymorphism may predict both Hb level and EPO need in HD patients. However, because the underlying mechanisms have not been clarified in the present study, further research on this issue is needed.
Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
Elevated calcium and phosphorus levels after therapy with injectable vitamin D for secondary hyperparathyroidism may accelerate vascular disease and hasten death in patients undergoing long-term hemodialysis. Paricalcitol, a new vitamin D analogue, appears to lessen the elevations in serum calcium and phosphorus levels, as compared with calcitriol, the standard form of injectable vitamin D.
We conducted a historical cohort study to compare the 36-month survival rate among patients undergoing long-term hemodialysis who started to receive treatment with paricalcitol (29,021 patients) or calcitriol (38,378 patients) between 1999 and 2001. Crude and adjusted survival rates were calculated and stratified analyses were performed. A subgroup of 16,483 patients who switched regimens was also evaluated.
The mortality rate among patients receiving paricalcitol was 3417 per 19,031 person-years (0.180 per person-year), as compared with 6805 per 30,471 person-years (0.223 per person-year) among those receiving calcitriol (P<0.001). The difference in survival was significant at 12 months and increased with time (P<0.001). In the adjusted analysis, the mortality rate was 16 percent lower (95 percent confidence interval, 10 to 21 percent) among paricalcitol-treated patients than among calcitriol-treated patients. A significant survival benefit was evident in 28 of 42 strata examined, and in no stratum was calcitriol favored. At 12 months, calcium and phosphorus levels had increased by 6.7 and 11.9 percent, respectively, in the paricalcitol group, as compared with 8.2 and 13.9 percent, respectively, in the calcitriol group (P<0.001). The two-year survival rate among patients who switched from calcitriol to paricalcitol was 73 percent, as compared with 64 percent among those who switched from paricalcitol to calcitriol (P=0.04).
Patients who receive paricalcitol while undergoing long-term hemodialysis appear to have a significant survival advantage over those who receive calcitriol. A prospective, randomized study is critical to confirm these findings.
Our recent studies suggest that 1,25-dihydroxyvitamin D3 functions as an endocrine suppressor of renin biosynthesis. Genetic disruption of the vitamin D receptor (VDR) results in overstimulation of the renin-angiotensin system (RAS), leading to high blood pressure and cardiac hypertrophy. Consistent with the higher heart-to-body weight ratio, the size of left ventricular cardiomyocytes in VDR knockout (KO) mice was markedly increased compared with wild-type (WT) mice. As expected, levels of atrial natriuretic peptide (ANP) mRNA and circulating ANP were also increased in VDRKO mice. Treatment of VDRKO mice with captopril reduced cardiac hypertrophy and normalized ANP expression. To investigate the role of the cardiac RAS in the development of cardiac hypertrophy, the expression of renin, angiotensinogen, and AT-1a receptor in the heart was examined by real-time RT-PCR and immunostaining. In VDRKO mice, the cardiac renin mRNA level was significantly increased, and this increase was further amplified by captopril treatment. Consistently, intense immunostaining was detected in the left ventricle of captopril-treated WT and VDRKO mice by use of an anti-renin antibody. Levels of cardiac angiotensinogen and AT-1a receptor mRNAs were unchanged in the mutant mice. These data suggest that the cardiac hypertrophy seen in VDRKO mice is a consequence of activation of both the systemic and cardiac RAS and support the notion that 1,25-dihydroxyvitamin D(3) regulates cardiac functions, at least in part, through the RAS.
The role of vitamin D in left ventricular hypertrophy and cardiac function. Cardiovascular disease is the leading cause of death among patients with end-stage renal disease (ESRD). Traditional cardiac risk factors, as well as other factors specific to the ESRD population such as hyperphosphatemia, elevated calcium and phosphate product, abnormal lipid metabolism, hyperhomocysteinemia, and chronic inflammation play a role in the excessive risk of cardiovascular death in this population. Left ventricular disorders are proven risk factors for cardiac mortality in hemodialysis patients. These disorders are present in incident ESRD patients at rates far above the general population. There is an accumulating body of evidence that suggests that vitamin D plays a role in cardiovascular disease. Abnormal vitamin metabolism, through deficiency of the active form of 1,25-dihydroxyvitamin D(3), and acquired vitamin D resistance through the uremic state, have been shown to be important in ESRD. Vitamin D deficiency has long been known to affect cardiac contractility, vascular tone, cardiac collagen content, and cardiac tissue maturation. Recent studies using vitamin D receptor deficient mice as a model demonstrate a crucial role of vitamin D in regulation of the renin-angiotensin system. Additionally, there is emerging evidence linking treatment with vitamin D to improved survival on hemodialysis and improvement in cardiac function. The emergence of this data is focusing attention on the previously underappreciated nonmineral homeostatic effects of vitamin D that very likely play an important role in the pathogenesis of cardiac disease in ESRD.
Background:
Sudden cardiac death is common in patients on hemodialysis (HD), and its rate is as high as 25% of all cardiac deaths associated with left ventricular hypertrophy (LVH) and secondary hyperparathyroidism. A prolonged QT interval on standard electrocardiography is related to an increase in sudden death in various patient groups. It is also well known that LVH has been noted in uremic patients with high parathyroid hormone levels.
Methods:
To evaluate the response of intravenous calcitriol treatment on the QT interval and LVH in HD patients with secondary hyperparathyroidism (intact parathyroid hormone, iPTH, > 450 ng/ml), echocardiographic, electrocardiographic (ECG), and biochemical assessments were performed over a 15-week period in 25 HD patients before and after intravenous calcitriol treatment. We also evaluated 25 age-, sex-, HD duration-, and BMI-matched HD control patients with secondary hyperparathyroidism.
Results:
In patients receiving intravenous calcitriol, a significant reduction in iPTH levels (p < 0.05) and alkaline phosphatase levels (p < 0.01) was found without changes in values of serum calcium and ionized Ca2+, phosphorus, Na+, K+, Mg2+, hematocrit, blood pressure, or other hemodynamic changes. Echocardiograms showed significant decreases in the thickness of the interventricular septum (p < 0.05), left posterior wall thickness (p < 0.05), and left ventricle mass index (LVMi, p < 0.01). In addition, sequential ECG measurement in patients with calcitriol treatment showed significant reductions in QTcmax (QTmax interval corrected for heart rates, p < 0.01) and QTc dispersion (QT dispersion corrected for heart rates, p < 0.01). However, in the control patients, biochemical, hemodynamic, and ECG changes, as well as myocardial structural and functional changes were not seen. Multiple regression analysis in all patients indicated that iPTH and LVMi levels were independent predictors of QTcmax while the LVMi level was the only independent predictor of QTc dispersion (p < 0.05).
Conclusions:
Our study showed a significant correlation between LVMi and QT dispersion in HD patients with secondary hyperparathyroidism. Intravenous calcitriol treatment, to be used for the control of secondary hyperparathyroidism, was found to cause regression of myocardial hypertrophy and a reduction in the QTc interval and dispersion, without biochemical and hemodynamic changes. These findings suggest that an active vitamin D metabolite has a cardioprotective action in HD patients.
Proteinuria is a marker of cardiovascular and renal disease in patients with chronic kidney disease (CKD), and reduction in proteinuria has been associated with improved cardiovascular and renal outcomes. While active vitamin D and its analogs have been shown to have renal protective effects in animals, these hormones have not been shown to reduce proteinuria in CKD patients.
In three double-blind, randomized, placebo-controlled studies to evaluate the safety and efficacy of oral paricalcitol, 220 CKD stage 3 and 4 patients with secondary hyperparathyroidism (SHPT) were randomized to oral paricalcitol (N= 107, mean dose 9.5 microg/week) or placebo (N= 113) and followed for up to 24 weeks. In conjunction with other safety measures, proteinuria was measured by dipstick and read by an automated reader at the beginning and end of trial. We subsequently analyzed the dipstick data to evaluate the effect of paricalcitol on proteinuria.
At baseline, proteinuria was present in 57 patients randomized to oral paricalcitol and 61 patients randomized to placebo (NS). At the final visit, 29/57 (51%) of the paricalcitol patients compared to 15/61 (25%) placebo patients had reduction in proteinuria, P= 0.004 (odds for reduction in proteinuria 3.2 times greater for paricalcitol patients, 95% CI 1.5-6.9). For the patients who had both proteinuria at baseline and parathyroid hormone (PTH) suppression (end point defined as 2 consecutive > or =30% decreases in iPTH from baseline), 27/51 (53%) patients had a reduction in the proteinuria in the paricalcitol group and 0/7 (0%) had a reduction in proteinuria in the placebo group. Reduction of proteinuria favored patients on paricalcitol, regardless of age, sex, race, diabetes mellitus, hypertension, or use of therapies to block the renin-angiotensin-aldosterone system (RAAS).
Our results demonstrate that the reduction in proteinuria was associated with paricalcitol treatment, and the reduction in proteinuria was independent of concomitant use of agents that block the RAAS. Paricalcitol as a potential pharmacologic means of reducing proteinuria in CKD patients warrants further investigation.
Hyperparathyroidism occurs in most patients during the progression of chronic kidney disease (CKD) and one of its initiating events, reduced serum levels of 1,25-dihydroxyvitamin D, results from a decrease in renal 1alpha hydroxylase activity, which converts 25-hydroxyvitamin D to its activated form. The combination of persistently high parathyroid hormone (PTH) and low 1,25-dihydroxyvitamin D is associated with bone loss, cardiovascular disease, immune suppression and increased mortality in patients with end-stage kidney failure. Recent studies in dialysis patients suggest that paricalcitol, a selective activator of the vitamin D receptor (VDR), is associated with a more favorable efficacy to side effect profile than calcitriol, with less morbidity and better survival. One hypothesis derived from such studies suggests that systemic activation of VDRs may have direct effects on the cardiovascular system to decrease mortality in CKD. Although current guidelines for regulating serum calcium, phosphate and PTH recommend specific interventions at the various stages of CKD to prevent or postpone irreversible parathyroid disease and decrease cardiovascular morbidity and mortality, emerging data suggest that vitamin D therapy may prolong survival in this patient population by mechanisms that are independent of calcium, phosphate and PTH. It is suggested that a re-evaluation of current treatment recommendations is needed and that future research should focus on mechanisms that distinguish potential tissue specific benefits of selective VDR activators in patients with CKD.
Although renal osteodystrophy and vitamin D analogs may be related to survival in maintenance hemodialysis (MHD) patients, most studies have examined associations between baseline values and survival without accounting for variations in clinical and laboratory measures over time. We examined associations between survival and quarterly laboratory values and administered paricalcitol in a 2-year (July 2001-June 2003) cohort of 58,058 MHD patients from all DaVita dialysis clinics in USA using both time-dependent Cox models with repeated measures and fixed-covariate Cox models with only baseline values. Whereas hypercalcemia and hyperphosphatemia were robust predictors of higher death risk in all models, the association between serum calcium and mortality was different in time-varying models. Changes in baseline calcium and phosphorus values beyond the Kidney Disease Outcome Quality Initiative recommended targets were associated with increased mortality. Associations between high serum parathyroid hormone and increased death risk were masked by case-mix characteristics of MHD patients. Time-varying serum alkaline phosphatase had an incremental association with mortality. Administration of any dose of paricalcitol was associated with improved survival in time-varying models. Controlling for nutritional markers may introduce overadjustment bias owing to their strong collinearity with osteodystrophy surrogates. Whereas both time-dependent and fixed-covariate Cox models result in similar associations between osteodystrophy indicators and survival, subtle but potentially clinically relevant differences between the two models exist, probably because fixed models do not account for variations of osteodystrophy indices and changes in medication dose over time.
Vitamin D receptor (VDR) gene polymorphisms have been widely studied, especially to analyze their effects on calcium-phosphorus metabolism and secondary hyperparathyroidism in patients on dialysis. In this study, we sought to investigate the possible effects of these polymorphisms on the anemia of renal failure and recombinant human erythropoietin (rHuEPO) responses among patients receiving hemodialysis.
One hundred twenty-eight patients (52 females/76 males) underwent genotyping for the insertion/deletion Bsml (B-->b, restriction site, exon VIII-->IX) and Tagl (T-->t, 352 exon IX) VDR gene polymorphisms. The mean value of the last 6 months' monthly evaluated laboratory values (C-reactive protein, hemoglobin, iron indices, PTH, and albumin) and clinical findings (rHuEPO requirement, cumulative iron supplementation doses, and body weight) were analyzed retrospectively excluding patients with chronic inflammation, hemolytic anemia, or active blood loss such as gastrointestinal bleeding.
Mean age and dialysis durations were 41.5 +/- 11.8 years and 91.8 +/- 45.3 months, respectively. Polymorphism percentages were as follows: Bsml; BB/Bb/bb: 32.2/63.6/4.2 and Tagl; TT/Tt/tt: 40.5/55.4/4.1%, respectively. BB variant of Bsml gene was related to lower rHuEPO needs (P < .05) and also higher hemoglobin levels (P < .005) when compared with the Bb/bb variant. Considering Tagl variants, transferrin saturation levels were lower (P < .03) among patients with the Tt/tt variant, but there was no other significant difference in the mean values of other data between TT and Tt/tt variants.
The BB variant of Bsml was related to decreased rHuEPO requirements to achieve higher hemoglobin levels among maintenance hemodialysis patients without chronic inflammation.