Cardiovascular Disease In Chronic Kidney Disease Research Articles

#1984 Extracellular vesicles drive loss of endothelial homeostasis in pediatric chronic kidney disease

Abstract Background and Aims Cardiovascular disease (CVD) is the main cause of mortality in chronic kidney disease (CKD). However, the pathogenesis of CVD in CKD remains incompletely understood. Extracellular vesicles (EVs) emerged as mediators of inter-organ cross-talk and endothelial EVs (EC-EVs) were previously associated with CVD. We hypothesized that CKD drives endothelial EV release in CKD and that these EC-EVs drive CVD in CKD. Method A cohort of 94 children (mean age 10.9 years) at different stages of CKD (patients with or without dialysis and after kidney transplantation (KTx)) and age-matched healthy donors was recruited, offering the unique opportunity to analyze cardiovascular effects of CKD and EV dynamics in absence of age-related comorbidities. Thorough characterization of plasma EVs by electron microscopy, nanoparticle tracking analysis (NTA), flow cytometry and miRNA sequencing was carried out. Functional properties of patient EVs and CKD-specific EV release mechanisms were tested in vitro. Results EC-EVs were elevated in hemodialysis (HD) patients (as measured by flow cytometry) while total EV counts showed higher concentrations in peritoneal dialysis patients (according to NTA). Longitudinal follow-ups revealed that EC-EVs decreased after receiving KTx. EV small RNA sequencing showed lower abundance of 30 microRNAs in EVs from CKD patients, most pronounced in HD patients compared to both healthy donors and KTx recipients. Downregulation of let-7d-5p, miR-19a-3p, miR-24-3p, miR-103a-3p and miR-142-3p was confirmed using RT-qPCR. Gene enrichment analyses predicted angiogenesis and smooth muscle cell (SMC) proliferation as targets of differentially regulated miRNAs in CKD. In vitro, angiogenesis of Human Umbilical Vein Endothelial Cells (HUVECs) was decreased upon treatment with CKD EVs as indicated by decreased vascular tube formation, endothelial migration and proliferation while SMC proliferation remained unchanged. To assess the putative role of uremic toxins for EV release in CKD, we focused on tryptophan metabolites and performed targeted plasma metabolomics that showed stage-dependent increases of uremic toxins of indole and kynurenine pathways in children with CKD, with highest levels in dialysis patients and almost normal levels after KTx. Uremic toxins indoxyl sulfate, formylkynurenine and xanthurenic acid correlated positively with EC-EVs in our cohort, but were not sufficient to trigger EV release from aortic endothelial cells alone. However, high shear stress together with indoxyl sulfate increased EV release from venous endothelial cells corresponding to higher endothelial EV concentrations in HD patients with arterio-venous fistulas (AVF) and recapitulated EV miRNA changes in vitro observed in CKD in vivo (lower abundance of let-7d-5p and miR-24-3p). Conclusion Endothelial EV release and decreased EV miRNAs associate with advanced CKD while increased endothelial shear stress and indoxyl sulfate form potential causative factors of altered EV phenotype. CKD EVs inhibit angiogenesis in vitro, potentially caused by dysregulated EV miRNAs that could form novel therapeutical targets to reduce CVD burden in CKD.

Gut-immune axis and cardiovascular risk in chronic kidney disease.

Patients with chronic kidney disease (CKD) suffer from marked cardiovascular morbidity and mortality, so lowering the cardiovascular risk is paramount to improve quality of life and survival in CKD. Manifold mechanisms are hold accountable for the development of cardiovascular disease (CVD), and recently inflammation arose as novel risk factor significantly contributing to progression of CVD. While the gut microbiome was identified as key regulator of immunity and inflammation in several disease, CKD-related microbiome-immune interaction gains increasing importance. Here, we summarize the latest knowledge on microbiome dysbiosis in CKD, subsequent changes in bacterial and host metabolism and how this drives inflammation and CVD in CKD. Moreover, we outline potential therapeutic targets along the gut-immune-cardiovascular axis that could aid the combat of CVD development and high mortality in CKD.

Sarcopenia predicts cardiovascular disease in chronic kidney disease at advanced stage and associated risks.

Chronic kidney disease (CKD) has been associated with a higher risk of cardiovascular disease (CVD), and sarcopenia is a new risk factor for CKD. However, whether sarcopenia predicts CVD in CKD remains to be determined. Sarcopenia would predict CVD in CKD at advanced stage. This analysis included 101 patients with CKD at stage 3 or over to determine the prevalence of sarcopenia and cardiovascular disease in patients with CKD at stage 3 or over in our center. The patients were further categorized into sarcopenia group (N = 19) and non-sarcopenia group (N = 82) according to the diagnostic criteria for sarcopenia. Data on demographics, laboratory tests, and measurements of extracardiac adipose tissue thickness (EAT) was collected. The prevalence of sarcopenia in patients with CKD at stage ≥ 3 was 19%. Compared with non-sarcopenia group, patients from the sarcopenia group were older (P = .005), and presented longer disease durations (P = .002). The serum level of albumin was significantly decreased, (P = .047), and high-sensitivity C-reactive protein level (CRP) was significantly increased (P = .003) in sarcopenia group. In addition, the EAT was thicker in the sarcopenia group compared with non-sarcopenia group (P = .032). Furthermore, the le-stratified atherosclerotic cardiovascular disease (ASCVD) risk scores were positively correlated with inflammation, nutrition, body mass index (BMI) and disease duration of CKD in sarcopenia group (P < .001). Patients with CKD are prone to have sacropenia, which is associated with inflammation and malnutrition. Presence of sarcopenia in CKD patients predicts the risk of ASCVD.

Cardiovascular aging in patients with chronic kidney disease: pathogenesis and potential therapeutics

Patients with chronic kidney dysfunction have an elevated risk for various cardiovascular diseases. Even in the early stages of chronic kidney disease (CKD) the prevalence of cardiovascular events and mortalities is extremely high if compared with age-matched general population. With worsening of kidney function this risk is growing intensely. There are many traditional and non-traditional risk factors that can lead to cardiovascular disease in CKD. Cardiovascular rather than kidney failure, per se, is the main cause of mortality in CKD. The increase of calcification promoters and the decrease of inhibitors leads to the development of vascular calcification in the early stages of CKD. In this regard, CKD mimics cardiovascular system aging with a premature onset and an accelerated progression.Various non-pharmacological and pharmacological interventions have been studied to retard premature cardiovascular aging in CKD. In this review article, we are summarizing the pathogenesis, risk factors, and possible management strategies of cardiovascular disease in CKD.

A deep learning system for retinal vessel calibre improves cardiovascular risk prediction in Asians with chronic kidney disease.

Cardiovascular disease (CVD) and mortality is elevated in chronic kidney disease (CKD). Retinal vessel calibre in retinal photographs is associated with cardiovascular risk and automated measurements may aid CVD risk prediction. Retrospective cohort study of 860 Chinese, Malay and Indian participants aged 40-80 years with CKD [estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2] who attended the baseline visit (2004-2011) of the Singapore Epidemiology of Eye Diseases Study. Retinal vessel calibre measurements were obtained by a deep learning system (DLS). Incident CVD [non-fatal acute myocardial infarction (MI) and stroke, and death due to MI, stroke and other CVD] in those who were free of CVD at baseline was ascertained until 31 December 2019. Risk factors (established, kidney, and retinal features) were examined using Cox proportional hazards regression models. Model performance was assessed for discrimination, fit, and net reclassification improvement (NRI). Incident CVD occurred in 289 (33.6%) over mean follow-up of 9.3 (4.3)years. After adjusting for established cardiovascular risk factors, eGFR [adjusted HR 0.98 (95% CI: 0.97-0.99)] and retinal arteriolar narrowing [adjusted HR 1.40 (95% CI: 1.17-1.68)], but not venular dilation, were independent predictors for CVD in CKD. The addition of eGFR and retinal features to established cardiovascular risk factors improved model discrimination with significantly better fit and better risk prediction according to the low (<15%), intermediate (15-29.9%), and high (30% or more) risk categories (NRI 5.8%), and with higher risk thresholds (NRI 12.7%). Retinal vessel calibre measurements by DLS were significantly associated with incident CVD independent of established CVD risk factors. Addition of kidney function and retinal vessel calibre parameters may improve CVD risk prediction among Asians with CKD.

Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Statins in Chronic Kidney Disease-Effects on Atherosclerosis and Cellular Senescence.

Chronic kidney disease (CKD) is a serious health problem that can affect various systems in the human body. Renal failure promotes mechanisms of premature cellular aging and also features of generalized inflammation in the body, which translates into a close relationship between kidney dysfunction and cardiovascular disease (CVD). As kidney function deteriorates, cardiovascular risk and mortality increase in this group of patients. Oxidative stress and inflammation are two closely related processes that initiate a vicious cycle by activating each other. Together with aging, they represent the key factors that cause and exacerbate CVD in CKD. Patients with CKD are particularly vulnerable to the accumulation of aging endothelial cells, vascular smooth muscle and macrophages, increasing the risk of atherosclerosis. Several mechanisms are known that can lead to the progression of the aforementioned problems, such as the accumulation of uremic toxins, persistent inflammation, impaired lipid and electrolyte metabolism, nitric oxide (NO) deficiency, the increased production of reactive oxygen species (ROS) and damage to deoxyribonucleic acid (DNA) and mitochondria. According to research, we can distinguish a group of drugs that effectively counteract the negative effects of CKD-statins. This is a group of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase and affect a number of cellular processes and pathways, resulting in the overall slowing of atherosclerosis and cellular aging.

Resveratrol supplementation improves endothelial function in chronic kidney disease

Introduction: Chronic kidney disease (CKD) associates with increased risk of cardiovascular disease (CVD), in part, due to lower endothelial function. Thus, interventions that increase endothelial function could mitigate CVD in CKD. Resveratrol is a polyphenol that improves endothelial function in obese and aging adults. Whether resveratrol supplementation increases endothelial function in patients with CKD is unknown. Our objective was to test the effects of resveratrol supplementation on endothelial function in CKD. We hypothesized that resveratrol supplementation would increase endothelial function in patients with CKD. Methods: 25 adults with stage 3 CKD and type 2 diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/day) on endothelial function. Endothelial function was assessed via brachial artery flow-mediated dilation (BA-FMD). Vascular smooth muscle reactivity was determined from nitroglycerin-mediated dilation. Estimated glomerular filtration rate (eGFR) was calculated from serum cystatin C using the CKD-EPI formula. A mixed effects generalized linear model was used to evaluate differences in treatment arms over time. Results: The median age of the subjects was 70 (67, 74) years and 86% of the patients were male. The mean (SD) GFR and hemoglobin A1c were 42(9) ml/min/1.73m2 and 7.36(0.77)%, respectively. Within-group comparisons revealed BA-FMD increased by 0.91% after resveratrol supplementation (p=0.002), but not placebo (p=0.44), and between-group comparisons indicate resveratrol increased BA-FMD greater than placebo (p=0.001). Nitroglycerin mediated dilation was unchanged after both resveratrol supplementation and placebo (p&gt;0.05). GFR, hemoglobin A1c and blood pressure were unchanged following resveratrol supplementation suggesting that other mechanisms may underlie resveratrol-mediated benefits on endothelial function in this study. Conclusion: Resveratrol supplementation increases endothelial function in patients with CKD. Larger clinical trials for longer duration are needed to confirm our findings and to evaluate the mechanisms by which resveratrol improves endothelial function in CKD. Funding: This study was supported by the Renal Hypertension Training Grant (NIH NRSA T32 award) and Dr. Jalal's grant R01HL134738-01A1. Colin Gimblet is supported by the American Heart Association predoctoral fellowship grant (23PRE1012593). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Cardio-Kidney Patient: Epidemiology, Clinical Characteristics and Therapy.

Patients with chronic kidney disease (CKD) are at high risk to develop cardiovascular disease with its manifestations coronary artery disease, heart failure, arrhythmias, and sudden cardiac death. In addition, the presence of CKD has a major impact on the prognosis of patients with cardiovascular disease, leading to an increased morbidity and mortality if both comorbidities are present. Therapeutic options including medical therapy and interventional treatment are often limited in patients with advanced CKD, and in most cardiovascular outcome trials, patients with advanced CKD have been excluded. Thus, in many patients, treatment strategies for cardiovascular disease need to be extrapolated from trials conducted in patients without CKD. The current article summarizes the epidemiology, clinical presentation, and treatment options for the most prevalent manifestations of cardiovascular disease in CKD and discusses the currently available treatment options to reduce morbidity and mortality in this high-risk population.

Involvement of lysyl oxidase in the pathogenesis of arterial stiffness in chronic kidney disease.

Patients with chronic kidney disease (CKD) are at increased risk for adverse cardiovascular events. CKD is associated with increases in arterial stiffness, whereas improvements in arterial stiffness correlate with better survival. However, arterial stiffness is increased early in CKD, suggesting that there might be additional factors, unique to kidney disease, that increase arterial stiffness. Lysyl oxidase (LOX) is a key mediator of collagen cross linking and matrix remodeling. LOX is predominantly expressed in the cardiovascular system, and its upregulation has been associated with increased tissue stiffening and extracellular matrix remodeling. Thus, this study was designed to evaluate the role of increased LOX activity in inducing aortic stiffness in CKD and whether β-aminopropionitrile (BAPN), a LOX inhibitor, could prevent aortic stiffness by reducing collagen cross linking. Eight-week-old male C57BL/6 mice were subjected to 5/6 nephrectomy (Nx) or sham surgery. Two weeks after surgery, mice were randomized to BAPN (300 mg/kg/day in water) or vehicle treatment for 4 wk. Aortic stiffness was assessed by pulse wave velocity (PWV) using Doppler ultrasound. Aortic levels of LOX were assessed by ELISA, and cross-linked total collagen levels were analyzed by mass spectrometry and Sircol assay. Nx mice showed increased PWV and aortic wall remodeling compared with control mice. Collagen cross linking was increased in parallel with the increases in total collagen in the aorta of Nx mice. In contrast, Nx mice that received BAPN treatment showed decreased cross-linked collagens and PWV compared with that received vehicle treatment. Our results indicated that LOX might be an early and key mediator of aortic stiffness in CKD.NEW & NOTEWORTHY Arterial stiffness in CKD is associated with adverse cardiovascular outcomes. However, the mechanisms underlying increased aortic stiffness in CKD are unclear. Herein, we demonstrated that 1) increased aortic stiffness in CKD is independent of hypertension and calcification and 2) LOX-mediated changes in extracellular matrix are at least in part responsible for increased aortic stiffness in CKD. Prevention of excess LOX may have therapeutic potential in alleviating increased aortic stiffness and improving cardiovascular disease in CKD.

Excess risk of cardiovascular events in patients in the United States vs. Japan with chronic kidney disease is mediated mainly by left ventricular structure and function

While patients receiving dialysis therapy in the United States are more likely to develop cardiovascular disease (CVD) than those in Japan, direct comparisons of patients with predialysis chronic kidney disease (CKD) are rare. To study this, we compared various outcomes in patients with predialysis CKD using data from the Chronic Renal Insufficiency Cohort (CRIC) and CKD Japan Cohort (CKD-JAC) studies and determined mediators of any differences. Candidate mediators included left ventricular (LV) indices assessed by echocardiography. Among 3125 CRIC and 1097 CKD-JAC participants, the mean LV mass index (LVMI) and ejection fraction (EF) were 55.7 and 46.6 g/m2 and 54% and 65%, respectively (both significant). The difference in body mass index (32 and 24 kg/m2, respectively) largely accounted for the differences in LVMI and C-reactive protein levels across cohorts. Low EF and high LVMI were significantly associated with subsequent CVD in both cohorts. During a median follow-up of five years, CRIC participants were at higher risk for CVD (adjusted hazard ratio [95% confidence interval]: 3.66 [2.74-4.89]) and death (4.69 [3.05-7.19]). A three-fold higher C-reactive protein concentration and higher phosphate levels in the United States cohort were moderately strong mediators of the differences in CVD. However, echocardiographic parameters were stronger mediators than these laboratory measures. LVMI, EF and their combination mediated the observed difference in CVD (27%, 50%, and 57%, respectively) and congestive heart failure (33%, 62%, and 70%, respectively). Thus, higher LV mass and lower EF, even in the normal range, were found to be predictive of CVD in CKD.

Circulating Metabolites and Cardiovascular Disease in Asians with Chronic Kidney Disease

Introduction: Chronic kidney disease (CKD) is a growing public health problem, with significant burden of cardiovascular disease and mortality. The risk of cardiovascular disease in CKD is elevated beyond that predicted by traditional cardiovascular risk factors, suggesting that other factors may account for this increased risk. Through metabolic profiling, this study aimed to investigate the associations between serum metabolites and prevalent cardiovascular disease in Asian patients with CKD to provide insights into the complex interactions between metabolism, cardiovascular disease and CKD. Methods: This was a single-center cross-sectional study of 1,122 individuals from three ethnic cohorts in the population-based Singapore Epidemiology of Eye Disease (SEED) study (153 Chinese, 262 Indians, and 707 Malays) aged 40–80 years with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m²). Nuclear magnetic resonance spectroscopy was used to quantify 228 metabolites from the participants’ serum or plasma. Prevalent cardiovascular disease was defined as self-reported myocardial infarction, angina, or stroke. Multivariate logistic regression identified metabolites independently associated with cardiovascular disease in each ethnic cohort. Metabolites with the same direction of association with cardiovascular disease in all three cohorts were selected and subjected to meta-analysis. Results: Cardiovascular disease was present in 275 (24.5%). Participants with cardiovascular disease tend to be male; of older age; with hypertension, hyperlipidemia, and diabetes; with lower systolic and diastolic blood pressure (BP); lower high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol than those without cardiovascular disease. After adjusting for age, sex, systolic BP, diabetes, total cholesterol, and HDL cholesterol, 10 lipoprotein subclass ratios and 6 other metabolites were significantly associated with prevalent cardiovascular disease in at least one cohort. Meta-analysis with Bonferroni correction for multiple comparisons found that lower tyrosine, leucine, and valine concentrations and lower cholesteryl esters to total lipid ratio in intermediate-density lipoprotein (IDL) were associated with cardiovascular disease. Conclusion: In Chinese, Indian, and Malay participants with CKD, prevalent cardiovascular disease was associated with tyrosine, leucine, valine, and cholesteryl esters to total lipid ratios in IDL. Increased cardiovascular risk in CKD patients may be contributed by altered amino acid and lipoprotein metabolism. The presence of CKD and ethnic differences may affect interactions between metabolites in health and disease, hence greater understanding will allow us to better risk stratify patients, and also individualize care with consideration of ethnic disparities.

Uremic toxin indoxyl sulfate induces dysfunction of vascular smooth muscle cells via integrin-β1/ERK signaling pathway.

Protein-bound uremic toxins (PBUTs) are reported to be one of the major culprits in chronic kidney disease-cardiovascular disease (CKD-CVD) development, yet its mechanism is not fully clear. Our previous study confirmed elevated expression of integrin-β1 (ITGβ1) in vascular smooth muscle cells of uremic patients. Thus, this study aimed to explore the relationship between PBUTs and ITGβ1 in uremic vasculature injury. Human umbilical vein smooth muscle cells (HUVSMCs) and endothelial cells (HUVECs) were treated with two representative PUBTs, indoxyl sulfate (IS) and p-cresyl sulfate (PC). Both cells were measured for the expression of ITGβ1 and downstream signaling pathways and assayed for proliferation, migration, adhesion and apoptosis. The IS treatments were observed with significantly up-regulated ITGβ1 in HUVSMCs but not in HUVECs, while PC did not induce ITGβ1 alteration in either HUVSMCs or HUVECs. Furthermore, overexpression of ITGβ1 revealed activated downstream signal-regulated kinase (ERK) signaling pathway with promoted focal adhesion, migration, proliferation but no apoptosis in HUVSMCs by IS. These functional and pathway alterations could be significantly suppressed by RNA interference of ITGβ1. More importantly, the application of ERK1/2 inhibitor significantly suppressed the focal adhesion, migration and proliferation of HUVSMCs. We first demonstrated that ITGβ1/ERK signaling pathway mediated abnormal focal adhesion, migration and proliferation of vascular smooth muscle cells stimulated by IS. ITGβ1/ERK signaling may serve as a novel therapeutic target for CKD-CVD.

POS-250 A RANDOMIZED TRIAL OF EFFECT OF CHOLECALCIFEROL SUPPLEMENTATION ON CARDIOVASCULAR DISEASE, INFLAMMATION, AND BONE METABOLISM MARKERS IN CKD: BASELINE CHARACTERISTICS OF FEASIBILITY PHASE

Studies have linked lower vitamin D levels with cardiovascular disease (CVD) and mortality in general population and chronic kidney disease (CKD). The preliminary evidence of vitamin D supplementation is encouraging but there is a huge void with respect to good quality long term data supporting the use of this promising intervention for translation into better outcomes for CVD in CKD. This study is exploring the effect of cholecalciferol supplementation on cardiovascular disease, markers of inflammation and bone metabolism in CKD. We present the baseline characteristics of feasibility phase of the trial. The study is a multicentric, prospective, randomized, placebo controlled, double blind trial in two parallel groups and feasibility phase is being done at Postgraduate Institute of Medical Education and Research, Chandigarh, India. The trial is registered at Clinical Trials Registry of India (CTRI/2019/05/019211). After a run-in period of 2 weeks, the enrolled subjects are randomized in 1:1 to receive either 60,000 IU/2 weeks of cholecalciferol or matching placebo. The subjects will be then followed up every three month till 3 years. The primary outcome of the study is a composite of major adverse cardiac events (MACE). Secondary outcome measures include all-cause mortality, need of RRT, change in hsCRP, IL-6, iPTH, FGF-23, bone specific alkaline phosphatase, and CTX-1. A total of 720 subjects have been screened till date. Out of 119 enrolled, 86 subjects have been randomized over 24 months period. 76% subjects have completed annual follow up at 12 months, 66% subjects - 15thmonths follow up, 40%- 18 months follow up, 26% subjects - 21 months follow up, 6% subjects – 24 months follow up. Baseline characteristics and serum biomarkers levels has been analysed in 80 subjects. Mean age of the subjects were 51.3 ± 12.2 years and 58.8 % were males. Serum haemoglobin levels were 11.6 ±1.7 g/dl. Mean eGFR was 26.3 (17.4, 35.1) ml/min/1.73m2. Outcome events were; MACE: 1 (due to CVD), death other than due to MACE: 1 (due to COVID 19), subjects with composite of all-cause death and non-fatal MACE: 2, subject with need of RRT:1 and subjects with composite of 50% decline in GFR or need of RRT: 3. 2 serious adverse events unrelated to study drug were reported during the course of study. Table: Baseline levels of various serum biomarkers Tabled 1CharacteristicsTotal (N = 80)Serum creatinine (mg/dL)2.7 ± 1.1Serum calcium (mg/dL)9.2 (8.8, 9.4)Serum inorganic phosphorous (mg/dL)3.8 (3.2, 4.2)Serum intact parathyroid hormone (pg/mL)172.0 (94.6, 327.9)Serum 25-hydroxyvitamin D3 (ng/mL)28.5 (22.6, 38.2)Bone alkaline phosphatase (U/L)29.7 (22.1, 43.7)Fibroblast growth factor-23 (pg/mL)131.0 (37.9, 139.7)C-reactive protein (ng/mL)4.4 (1.9, 7.6)Interleukin-6 (pg/mL)4.0 (2.1, 2.3)Carboxy terminal telopeptide (ng/mL)1.2 (0.2, 2.3) Open table in a new tab Despite COVID 19 related restrictions being in place for most of the last 18 months, the study has been able to screen and enrol participants. The follow ups have been ensured either through physical or remote (mobile/telephonic) means. Once in the multi-centric phase, the study will be able to test a relatively inexpensive intervention in the form of vitamin D supplementation for CVD in CKD.

Vascular Calcification in Chronic Kidney Disease PatientsA Cross-sectional Study

Introduction: Vascular Calcification (VC) is considered as a cardiovascular risk marker in Chronic Kidney Disease (CKD) patients. VC is a process characterised by thickening and loss of elasticity of muscular arteries walls. The three pathological forms of cardiovascular disease in CKD are cardiac geometry, atherosclerosis and arteriosclerosis of the large vessels (carotid artery or aorta). Aim: To evaluate VC as a cardiovascular risk marker in CKD patients. Materials and Methods: This cross-sectional study was conducted in the Nephrology Department at Sri Ramachandra Medical College and Research Institute, Chennai, Tamil Nadu, India, from November 2019 to December 2020. The study included 27 CKD patients who were on maintenance haemodialysis. The participants were 20 to 70 years of age, and of both genders. The Intima Media Thickness (IMT) was assessed by ultrasonography. Peak Systolic Velocity (PSV) measurement was done using doppler ultrasonography. Both the measurements were done on common Carotid Artery (CCA), and Internal Carotid Artery (ICA) on both sides of the neck. Student’s t-test and Chi-square test was used in this study. Data were expressed as mean±SD. The p-value &lt;0.05 was considered as statistically significant. Results: Out of 27 study participants, 20 (74%) were male and females were 7 (26%), with mean age of 48 years. There was significant increase in IMT of the ICA on the right side of the neck compared to left side (p-value=0.01). Also, there was significant increase in PSV of ICA on the right side compared to left side of the neck (p-value=0.04). There were no statistically significant differences in IMT and PSV when CCA on the right side was compared to that of the left side of the neck. Conclusion: The IMT was increased in ICA and CCA. But there was statistically significant difference only in ICA, where it was more prominent on the right side compared to left side. CKD patients on haemodialysis management could have the risk factors in the form of increased IMT predisposing them to early mortality from cardiovascular complications.

Comparative analysis of fibroblast growth Factor-23 as a correlate of cardiovascular disease among individuals with chronic kidney disease, hypertensives, and healthy controls.

Chronic kidney disease (CKD) is a global growing public health epidemic with attending morbidity and huge financial cost. Cardiovascular disease (CVD), a major complication of CKD, contributes to its excessive mortality rate. The aetio-pathogenesis of the excess burden of CVD in CKD is a feature yet to be unravelled. Fibroblast growth factor-23 (FGF-23) has been implicated as a risk factor for CVD among patients with CKD. However, most of these studies were predominantly among the Caucasian population. This study aims to determine the correlation between FGF-23 and CVD among Nigerians with CKD. A cross-sectional comparative study composed of three groups: participants with CKD, hypertensives without CKD, and healthy individuals, represented as group 1, 2, and 3, respectively. Information obtained included demographic data and occurrence of risk factors for CVD. Cardiovascular risks were assessed by echocardiography and all the participants had kidney function tests done with plasma FGF-23. The study sample size consisted of 135 participants. The mean (SD) age for participants with CKD and controls were 50.2 (12.7), 54.3 (15.5), and 40.2 (14.1) years, respectively. The median [interquartile range (IQR)] of plasma FGF-23 for participants with CKD 210 (139-304) RU/ml, and controls 124 (86-170) RU/ml, and 71 (38 - 89) RU/ml P < 0.001. Most participants with CKD had left ventricular hypertrophy (LVH) (80.0%), compared to the controls; 28.9% and 6.7% P < 0.001. Similarly, majority of participants with CKD had elevated plasma FGF-23 with LVH (85.7%) compared to controls 55.6% and 11.5%, whereas for aortic valve calcification with elevated plasma FGF-23 among CKD and controls were 53.6% (P = 0.29), 37.0% (P = 0.03), and 19.2% (P = 0.06), respectively. Individuals with CKD had frequencies of elevated plasma FGF-23, LVH, and cardiac valve calcification, which are surrogates of cardiovascular events.

Sesamol Ameliorates Renal Injury-Mediated Atherosclerosis via Inhibition of Oxidative Stress/IKKα/p53.

Patients with chronic kidney disease (CKD) are at an increased risk of premature death due to the development of cardiovascular disease (CVD) owing to atherosclerosis-mediated cardiovascular events. However, the mechanisms linking CKD and CVD are clear, and the current treatments for high-risk groups are limited. In this study, we aimed to examine the effects of sesamol, a natural compound extracted from sesame oil, on the development of atherosclerosis in a rodent CKD model, and reactive oxygen species-induced oxidative damage in an endothelial cell model. ApoE–/– mice were subjected to 5/6 nephrectomy (5/6 Nx) and administered sesamol for 8 weeks. Compared with the sham group, the 5/6 Nx ApoE–/– mice showed a significant increase in malondialdehyde levels and Oil Red O staining patterns, which significantly decreased following sesamol administration. Sesamol suppressed H2O2-induced expression of phospho-IKKα, p53, and caspase-3. Our results highlight the protective role of sesamol in renal injury-associated atherosclerosis and the pathological importance of oxidative stress burden in CKD–CVD interaction.

The intersection of mineralocorticoid receptor activation and the FGF23-Klotho cascade: a duopoly that promotes renal and cardiovascular injury.

The nexus of chronic kidney disease (CKD) and cardiovascular disease (CVD) amplifies the morbidity and mortality of CKD, emphasizing the need for defining and establishing therapeutic initiatives to modify and abrogate the progression of CKD and concomitant CV risks. In addition to the traditional CV risk factors, disturbances of mineral metabolism are specific risk factors that contribute to the excessive CV mortality in patients with CKD. These risk factors include dysregulations of circulating factors that modulate phosphate metabolism, including fibroblast growth factor 23 (FGF23) and soluble Klotho. Reduced circulating levels and suppressed renal Klotho expression may be associated with adverse outcomes in CKD patients. While elevated circulating concentrations or locally produced FGF23 in the strained heart exert prohypertrophic mechanisms on the myocardium, Klotho attenuates tissue fibrosis, progression of CKD, cardiomyopathy, endothelial dysfunction, vascular stiffness and vascular calcification. Mineralocorticoid receptor (MR) activation in nonclassical targets, mediated by aldosterone and other ligands, amplifies CVD in CKD. In concert, we detail how the interplay of elevated FGF23, activation of the MR and concomitant reductions of circulating Klotho in CKD may potentiate each other's deleterious effects on the kidney and heart, thereby contributing to the initiation and progression of kidney and cardiac functional deterioration, acting through multipronged, albeit complementary, mechanistic pathways.

Atherosclerotic Vascular Disease Associated with Chronic Kidney Disease.

Cardiovascular risk increases as glomerular filtration rate (GFR) declines in progressive renal disease and is maximal in patients with end-stage renal disease requiring maintenance dialysis. Atherosclerotic vascular disease, for which hyperlipidemia is the main risk factor and lipid-lowering therapy is the key intervention, is common. However, the pattern of dyslipidemia changes with low GFR and the association with vascular events becomes less clear. While the pathophysiology and management of patients with early chronic kidney disease (CKD) is similar to the general population, advanced and end-stage CKD is characterized by a disproportionate increase in fatal events, ineffectiveness of statin therapy, and greatly increased risk associated with coronary interventions. The most effective strategies to reduce atherosclerotic cardiovascular disease in CKD are to slow the decline in renal function or to restore renal function by transplantation.

Metabolic Acidosis and Cardiovascular Disease in CKD

Rationale & ObjectiveMetabolic acidosis related to chronic kidney disease (CKD) is associated with an accelerated decline in glomerular filtration rate (GFR) and the development of end-stage kidney disease. Whether metabolic acidosis is associated with cardiovascular (CV) events in patients with CKD is unclear.Study DesignRetrospective cohort study.Setting & ParticipantsThe Optum De-identified Electronic Health Records Dataset, 2007–2017, was used to generate a cohort of patients with non-dialysis-dependent CKD who had at least 3 estimated GFR < 60 mL/min/1.73 m2. Patients with metabolic acidosis (serum bicarbonate 12 to <22 mEq/L) or normal serum bicarbonate (22‒29 mEq/L) at baseline were identified by 2 consecutive measurements 28‒365 days apart.PredictorSerum bicarbonate as a continuous variable.OutcomePrimary outcome was a composite of major adverse cardiovascular events (MACE+). Secondary outcomes included individual components of the composite outcome.Analytical ApproachCox proportional hazards models to evaluate the association between 1-mEq/L increments in serum bicarbonate and MACE+.ResultsA total of 51,558 patients were evaluated, 34% had metabolic acidosis. The median follow-up period was 3.9–4.5 years, depending on the outcome assessed. The adjusted hazard ratio (HR) for MACE+ was 0.964 (95% CI, 0.961–0.968). For the individual components of incident heart failure (HF), stroke, myocardial infarction (MI), and CV death, HRs were 0.98 (95% CI, 0.97–0.98), 0.98 (95% CI, 0.97–0.99), 0.96 (95% CI, 0.96–0.97), and 0.94 (95% CI, 0.93–0.94), respectively, for every 1-mEq/L increase in serum bicarbonate.LimitationsPossible residual confounding.ConclusionsMetabolic acidosis in CKD is associated with an increased risk of MACE+ as well as the individual components of incident HF, stroke, MI, and CV death. Randomized controlled trials evaluating treatments for the correction of metabolic acidosis in CKD to prevent CV events are needed.