Treating endothelial dysfunction with vitamin D in chronic kidney disease: a meta-analysis.
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ABSTRACT: Vitamin D deficiency is common in patients with chronic kidney disease (CKD), and is associated with endothelial dysfunction and cardiovascular disease. We performed a meta-analysis to assess the effect of vitamin D treatment on flow mediated vasodilation (FMD) in CKD patients.PubMed/Medline, Web of Science, Embase and Cochrane trials and reviews were searched systematically for randomized controlled trials (RCT:s) using any vitamin D compound, at any stage of CKD, with FMD as outcome. Fixed and random effects models were performed using the standardized mean difference effect size post treatment for each trial. Heterogeneity was assessed by I2 statistics.4 trials were included, comprising 305 patients. One used both 1 and 2 ?g for two intervention groups and was therefore split in two during the analysis. Patients in the included trials had a mean age of 44-65 years and were all in CKD 3 to 4. One study used cholecalciferol, the others all used paricalcitol as treatment. Study duration was 12-16 weeks. Intervention with vitamin D was associated with ameliorated FMD (STANDmean ES 0.78, 95% CI 0.55-1.01) in a fixed model. Heterogeneity was substantial (I2 =?84%). Secondary analysis with random model analysis also showed significant results.Short term intervention with vitamin D is associated with improvements in endothelial function, as measured by FMD. This indicates positive effects of vitamin D on vascular disease in CKD. Limitations of this meta-analysis are the small number of studies performed, and the short duration of intervention.
<h4>Background</h4>Vitamin D deficiency is common in patients with chronic kidney disease (CKD), and is associated with endothelial dysfunction and cardiovascular disease. We performed a meta-analysis to assess the effect of vitamin D treatment on flow mediated vasodilation (FMD) in CKD patients.<h4>Methods</h4>PubMed/Medline, Web of Science, Embase and Cochrane trials and reviews were searched systematically for randomized controlled trials (RCT:s) using any vitamin D compound, at any stage of ...[more]
Project description:The interrelationship of multiple endothelial biomarkers and chronic kidney disease (CKD) has not been well studied. We measured asymmetric dimethylarginine (ADMA), L-arginine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), von Willebrand factor (vWF), flow-mediated dilation (FMD), and nitroglycerin-induced dilation (NID) in 201 patients with CKD and 201 community-based controls without CKD. Multivariable analyses were used to examine the interrelationship of endothelial biomarkers with CKD. The multivariable-adjusted medians (interquartile ranges) were 0.54 (0.40, 0.75) in patients with CKD vs. 0.25 (0.22, 0.27) μmol /L in controls without CKD (p<0.0001 for group difference) for ADMA; 67.0 (49.6, 86.7) vs. 31.0 (27.7, 34.2) μmol/L (p<0.0001) for L-arginine; 230.0 (171.6, 278.6) vs. 223.9 (178.0, 270.6) ng/mL (p=0.55) for sICAM-1; 981.7 (782.6, 1216.8) vs. 633.2 (507.8, 764.3) ng/mL (p<0.0001) for sVCAM-1; 47.9 (35.0, 62.5) vs. 37.0 (28.9, 48.0) ng/mL (p=0.01) for sE-selectin; 1320 (1044, 1664) vs. 1083 (756, 1359) mU/mL (p=0.008) for vWF; 5.74 (3.29, 8.72) vs. 8.80 (6.50, 11.39)% (p=0.01) for FMD; and 15.2 (13.5, 16.9) vs. 19.1 (17.2, 21.0)% (p=0.0002) for NID, respectively. In addition, the severity of CKD was positively associated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF and inversely associated with FMD and NID. Furthermore, FMD and NID were significantly and inversely correlated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF. In conclusion, these data indicate that multiple dysfunctions of the endothelium were present among patients with CKD. Interventional studies are warranted to test the effects of treatment of endothelial dysfunction on CKD.
Project description:BACKGROUND. Chronic kidney disease (CKD) is strongly associated with cardiovascular disease and there is an established association between vasculopathy affecting the kidney and eye. Optical coherence tomography (OCT) is a novel, rapid method for high-definition imaging of the retina and choroid. Its use in patients at high cardiovascular disease risk remains unexplored. METHODS. We used the new SPECTRALIS OCT machine to examine retinal and retinal nerve fiber layer (RNFL) thickness, macular volume, and choroidal thickness in a prospective cross-sectional study in 150 subjects: 50 patients with hypertension (defined as a documented clinic BP greater than or equal to 140/90 mmHg (prior to starting any treatment) with no underlying cause identified); 50 with CKD (estimated glomerular filtration rate (eGFR) 8-125 ml/min/1.73 m2); and 50 matched healthy controls. We excluded those with diabetes. The same, masked ophthalmologist carried out each study. Plasma IL-6, TNF-? , asymmetric dimethylarginine (ADMA), and endothelin-1 (ET-1), as measures of inflammation and endothelial function, were also assessed. RESULTS. Retinal thickness, macular volume, and choroidal thickness were all reduced in CKD compared with hypertensive and healthy subjects (for retinal thickness and macular volume P < 0.0001 for CKD vs. healthy and for CKD vs. hypertensive subjects; for choroidal thickness P < 0.001 for CKD vs. healthy and for CKD vs. hypertensive subjects). RNFL thickness did not differ between groups. Interestingly, a thinner choroid was associated with a lower eGFR (r = 0.35, P <0.0001) and, in CKD, with proteinuria (r = -0.58, P < 0.001) as well as increased circulating C-reactive protein (r = -0.57, P = 0.0002), IL-6 (r = -0.40, P < 0.01), ADMA (r = -0.37, P = 0.02), and ET-1 (r = -0.44, P < 0.01). Finally, choroidal thinning was associated with renal histological inflammation and arterial stiffness. In a model of hypertension, choroidal thinning was seen only in the presence of renal injury. CONCLUSIONS. Chorioretinal thinning in CKD is associated with lower eGFR and greater proteinuria, but not BP. Larger studies, in more targeted groups of patients, are now needed to clarify whether these eye changes reflect the natural history of CKD. Similarly, the associations with arterial stiffness, inflammation, and endothelial dysfunction warrant further examination. TRIAL REGISTRATION. Registration number at www.clinicalTrials.gov: NCT02132741. SOURCE OF FUNDING. TR was supported by a bursary from the Erasmus Medical Centre, Rotterdam. JJMHvB was supported by a bursary from the Utrecht University. JRC is supported by a Rowling Scholarship. SB was supported by a Wellcome Trust funded clinical research fellowship from the Scottish Translational Medicine and Therapeutics Initiative, and by a Rowling Scholarship, at the time of this work. ND is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/13/30/29994).
Project description:Allopurinol ameliorates endothelial dysfunction and arterial stiffness among patients without chronic kidney disease (CKD), but it is unknown if it has similar effects among patients with CKD. Furthermore, because arterial stiffness increases left ventricular afterload, any allopurinol-induced improvement in arterial compliance might also regress left ventricular hypertrophy (LVH). We conducted a randomized, double-blind, placebo-controlled, parallel-group study in patients with stage 3 CKD and LVH. We randomly assigned 67 subjects to allopurinol at 300 mg/d or placebo for 9 months; 53 patients completed the study. We measured left ventricular mass index (LVMI) with cardiac magnetic resonance imaging (MRI), assessed endothelial function by flow-mediated dilation (FMD) of the brachial artery, and evaluated central arterial stiffness by pulse-wave analysis. Allopurinol significantly reduced LVH (P=0.036), improved endothelial function (P=0.009), and improved the central augmentation index (P=0.015). This study demonstrates that allopurinol can regress left ventricular mass and improve endothelial function among patients with CKD. Because LVH and endothelial dysfunction associate with prognosis, these results call for further trials to examine whether allopurinol reduces cardiovascular events in patients with CKD and LVH.
Project description:Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.
Project description:BACKGROUND:Recent studies have demonstrated that there is an association between prehypertension and an increased risk of end-stage renal disease. However, there is conflicting evidence regarding the relationship between prehypertension and chronic kidney disease (CKD). This meta-analysis aimed to demonstrate the association between prehypertension and the incidence of CKD and identify the impacts of gender and ethnic differences. METHODS:MEDLINE, EMBASE, Cochrane Library (from inception through March 2016) and article reference lists were searched for relevant studies regarding blood pressure and CKD. Blood pressure (BP) measurements were classified as follows: optimal BP (less than 120/80 mmHg), prehypertension (120-139/80-89 mmHg) and hypertension (over 140/90 mmHg). CKD was defined by estimated glomerular filtration rate (eGFR)<60 ml/min/1.73 m2 or proteinuria. Two investigators independently extracted the data and assessed the quality of studies enrolled in this meta-analysis using the Newcastle-Ottawa Scale (NOS). We performed the meta-analysis using Stata/SE 12.0 (StataCorp LP). The random-effect models were used in the heterogeneous analyses. RESULTS:After retrieving data from 4,537 potentially relevant articles, we identified 7 cohort studies including 261,264 subjects, according to the predefined selection criteria. Five studies were conducted in Mongolians from East Asia, and the other two studies were performed in Indo-Europeans from Austria and Iran. The participants ranged in age from 20 to 89 years, and the proportion of females ranged from 27.2% to 63.8%. The follow-up period ranged from 2 to 11 years. Compared with the optimal BP values, prehypertension showed an increased risk of CKD (pooled RR = 1.28; 95% CI = 1.13-1.44; P = 0.000; I2 = 77.9%). In the sex-stratified analysis, we found a similar trend in women (pooled RR = 1.29; 95% CI = 1.01-1.63; P = 0.039; I2 = 76.1%) but not in men. This effect was observed only in Mongolians from East Asia (pooled RR = 1.37; 95% CI = 1.18-1.59; P = 0.000; I2 = 81.3%) and not in Indo-Europeans. CONCLUSIONS:Prehypertension is considered a potential cause of CKD. Gender and ethnic differences are exhibited in this association.
Project description:Renal disease is the common denominator of a number of underlying disease conditions, whose prevalence has been dramatically increasing over the last two decades. Two aspects are particularly relevant to the subject of this review: (I) most cases are gathered under the umbrella of chronic kidney disease since they require-predictably for several lustrums-continuous clinical monitoring and treatment to slow down disease progression and prevent complications; (II) cardiovascular disease is a terrible burden in this population of patients, in that it claims many lives yearly, while only a scant minority reach the renal disease end stage. Why indeed a review on DNA methylation and renal disease? As we hope to convince you, the present evidence supports the role of the existence of various derangements of the epigenetic control of gene expression in renal disease, which hold the potential to improve our ability, in the future, to more effectively act toward disease progression, predict outcomes and offer novel therapeutic approaches.
Project description:Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2?, PGD?, and PGE?, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD? and PGF?? were associated with reduced eGFR, whereas 8-isoprostane and again PGF?? were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.
Project description:Acute kidney injury may increase the risk for chronic kidney disease and end-stage renal disease. In an attempt to summarize the literature and provide more compelling evidence, we conducted a systematic review comparing the risk for CKD, ESRD, and death in patients with and without AKI. From electronic databases, web search engines, and bibliographies, 13 cohort studies were selected, evaluating long-term renal outcomes and non-renal outcomes in patients with AKI. The pooled incidence of CKD and ESRD were 25.8 per 100 person-years and 8.6 per 100 person-years, respectively. Patients with AKI had higher risks for developing CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1-25.5), ESRD (pooled adjusted HR 3.1, 95% CI 1.9-5.0), and mortality (pooled adjusted HR 2.0, 95% CI 1.3-3.1) compared with patients without AKI. The relationship between AKI and CKD or ESRD was graded on the basis of the severity of AKI, and the effect size was dampened by decreased baseline glomerular filtration rate. Data were limited, but AKI was also independently associated with the risk for cardiovascular disease and congestive heart failure, but not with hospitalization for stroke or all-cause hospitalizations. Meta-regression did not identify any study-level factors that were associated with the risk for CKD or ESRD. Our review identifies AKI as an independent risk factor for CKD, ESRD, death, and other important non-renal outcomes.
Project description:BackgroundAlthough the relationship between a history of kidney stones and chronic kidney disease (CKD) has been explored in many studies, it is still far from being well understood. Thus, we conducted a meta-analysis of studies comparing rates of CKD in patients with a history of kidney stones.MethodsPubMed, EMBASE, and the reference lists of relevant articles were searched to identify observational studies related to the topic. A random-effects model was used to combine the study-specific risk estimates. We explored the potential heterogeneity by subgroup analyses and meta-regression analyses.ResultsSeven studies were included in this meta-analysis. Pooled results suggested that a history of kidney stones was associated with an increased adjusted risk estimate for CKD [risk ratio (RR), 1.47 95% confidence interval (CI) [1.23-1.76])], with significant heterogeneity among these studies (I2 = 93.6%, P < 0.001). The observed positive association was observed in most of the subgroup analyses, whereas the association was not significant among studies from Asian countries, the mean age ≥50 years and male patients.ConclusionA history of kidney stones is associated with increased risk of CKD. Future investigations are encouraged to reveal the underlying mechanisms in the connection between kidney stones and CKD, which may point the way to more effective preventive and therapeutic measures.
Project description:BACKGROUND:Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated. METHODS:We assessed non-diabetic patients with CKD stage 3/4, age 17-80 years and serum 25(OH)D <75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks. RESULTS:Clinical characteristics of 26 patients were: age 50±14 (mean±1SD) years, eGFR 41±11 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%. At 16-week serum 25(OH)D and calcium increased (43±16 to 84±29 nmol/L, p<0.001 and 2.37±0.09 to 2.42±0.09 mmol/L; p?=?0.004, respectively) and parathyroid hormone decreased (10.8±8.6 to 7.4±4.4; p?=?0.001). FMD improved from 3.1±3.3% to 6.1±3.7%, p?=?0.001. Endothelial biomarker concentrations decreased: E-Selectin from 5666±2123 to 5256±2058 pg/mL; p?=?0.032, ICAM-1, 3.45±0.01 to 3.10±1.04 ng/mL; p?=?0.038 and VCAM-1, 54±33 to 42±33 ng/mL; p?=?0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged. CONCLUSION:This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23. TRIAL REGISTRATION:ClinicalTrials.gov NCT02005718.
