Atherosclerosis In Chronic Kidney Disease Patients Research Articles

Predictive value of the neutrophil percentage-to-albumin ratio for coronary atherosclerosis severity in patients with CKD

BackgroundThe neutrophil percentage-to-albumin ratio (NPAR), which is defined as the percentage of neutrophils divided by the concentration of albumin, is a cost-effective and readily available biomarker of inflammation. This study aimed to evaluate the association between the NPAR and the severity of coronary atherosclerosis in patients with chronic kidney disease (CKD).MethodsA total of 280 CKD patients who underwent coronary angiography were retrospectively enrolled in this study. The severity of coronary atherosclerosis was evaluated using the Gensini score (GS). Patients were divided into low-, medium- and high-NPAR groups according to the tertiles of the NPAR values. Logistic regression analysis was conducted to analyze the relationship between the NPAR and the GS. The cutoff points for the sensitivity and specificity of the NPAR in predicting the GS were estimated via receiver operating characteristic (ROC) analysis.ResultsThere was a higher prevalence of coronary artery disease (CAD) among CKD patients with higher NPARs (P =0.041). More patients in the high-NPAR group had complex CAD (triple-vessel disease and/or left main coronary artery stenosis) and chronic total occlusion lesions, and more of these patients required revascularization therapy (P<0.05). Multivariate logistic regression analysis revealed a significant positive correlation between the NPAR and the severity of coronary stenosis (adjusted OR 2.68, 95% CI 1.25-5.76, p=0.012), particularly among female and older (age ≥65) patients. The ROC analysis indicated that the optimal cutoff value for the NPAR in predicting severe coronary artery stenosis (GS>60) in CKD patients was 1.91 (sensitivity 0.495, specificity 0.749), with an area under the curve (AUC) of 0.650 (95% CI 0.581-0.719, P<0.001). A subgroup analysis according to sex revealed that the NPAR exhibited stronger predictive value in female patients (AUC 0.730, 95% CI 0.643-0.817) than in male patients (AUC 0.565, 95% CI 0.460-0.670) (P<0.001), and the optimal cutoff value for the NPAR in female patients was 1.80 (sensitivity 0.667, specificity 0.705).ConclusionsOur study demonstrated that the NPAR is independently associated with the severity of coronary atherosclerosis in CKD patients, especially in female and elderly patients (≥65 years old). Moreover, the NPAR can effectively predict the severity of coronary atherosclerosis, exhibiting greater predictive value in females than in males.

Matrix Gla protein polymorphism rs1800802 is associated with atheroma plaque progression and with cardiovascular events in a chronic kidney disease cohort.

Chronic kidney disease (CKD) is associated with increased atherosclerotic burden and higher risk for cardiovascular events (CVE). Atherosclerosis has a significant genetic component and, in CKD, it is influenced by mineral metabolism alterations. Therefore, genetic modifications of mineral metabolism-related proteins could affect atherosclerosis in CKD patients. In the present study we investigated the role of single nucleotide polymorphisms (SNPs) of the matrix gamma-carboxy glutamic acid protein (MGP) on atherosclerosis progression and CVE in a CKD cohort. A total of 2187 CKD patients from the Observatorio Nacional de Aterosclerosis en Nefrologia (NEFRONA) study were genotyped for SNPs present in the matrix gamma-carboxy glutamic acid (Gla) protein (MGP) gene. Atheromatosis was detected by vascular ultrasound. Progression of atheromatosis, defined as an increase in territories with plaque, was assessed after 24 months. Patients were followed for 48 months for CVE. Association of SNPs with plaque progression was assessed by logistic regression and their capacity to predict CVE by Cox regression. Three SNPs of the MGP gene were analyzed. No association of the rs4236 or the rs1800801 SNPs was detected with any of the outcomes. However, patients homozygotes for the minor allele of the rs1800802 SNP showed higher adjusted risk for plaque progression [odds ratio 2.3 (95% confidence interval 1.06-4.9)] and higher risk of suffering a CVE [hazard ratio 2.16 (95% confidence interval 1.13-4.12)] compared with the rest of genotypes. No association of the SNP with total or dp-ucMGP levels was found in a subsample. The rs1800802 polymorphism of MGP is associated with plaque progression and CVE in CKD patients.

The relationship between asymptomatic atherosclerosis and hepcidin-25 in chronic kidney disease patients.

The most common and lethal consequence of chronic kidney disease (CKD) is atherosclerotic cardiovascular disease. The persistent inflammation present in CKD increases hepcidin levels. Iron accumulates in the arterial wall in atherosclerosis. Hepcidin-25 was thought to accelerate the development of atherosclerotic plaques by blocking iron release from macrophages. Therefore, we sought to determine the relationship between hepcidin-25 and asymptomatic atherosclerosis in non-dialysis CKD patients. Investigate the relationship between hepcidin-25 and subclinical atherosclerosis in non-dialysis CKD patients. Cross-sectional SETTINGS: Outpatient clinic for urology and nephrology at a university hospital SUBJECTS AND METHODS: Participants above the age of 18 years included a group of healthy controls and a group of CKD patients who were not routinely maintained on hemodialysis. The latter group was further divided according to eGFR into CKD-3, CKD-4 and CKD-5 subgroups. We excluded patients with comorbidities, patients with chronic liver disease, and other conditions or habits. CBC, kidney function tests, and serum levels of hepcidin-25 (SH-25), TNF-α, IL-6, high-sensitivity C-reactive protein (hs-CRP), TC, TG, LDL-C and HDL-C were assessed. To measure carotid intima media thickness (CIMT) and determine presence of plaques, carotid ultrasonography was performed. The near or far walls of common carotid artery, bulb, and internal carotid artery were used to measure CIMT. SH-25 association and indicators of subclinical atherosclerosis. 128 participants, the control group (n=25) and the non-hemodialysis CKD patients (n=103) RESULTS: The CKD patients had significantly higher serum levels of markers of inflammation including IL-6, TNF-α, and hs-CRP (P<.001 for each) compared to the controls. There was a significantly higher level of TC, TG and LDL-C (P<.001 for each) and a lower level of HDL-C (P<.001) in the CDK patients compared to controls. SH-25 was considerably higher in all CKD subgroups, especially with progression of CKD. CIMT was increased in CKD patients especially CKD-4 and CKD-5 subgroups when compared to healthy participants (P<.001 for each). In the patient group, CIMT showed a positive correlation with SH-25, (r=.65 and P<.001), IL-6 (r=.65, P<.001), TNF-α (r=.71, P<.001), and hs-CRP (r=.52, P<.001). The ROC curve study showed that SH-25 (AUC=.86, P<.001), IL-6 (AUC=.83, P<.001), hs-CRP (AUC=.72, P<.001), TNF-α (AUC=.82, P<.001) were strong predictors of subclinical atherosclerosis in the CKD patients. SH-25 and CIMT had a positive relationship in CKD patients. The ROC curve showed that SH-25 is a reliable predictor of carotid atherosclerosis. Therefore, we suggest that SH-25 is a vital biomarker of asymptomatic atherosclerosis. Single-center.

Clinical Factors Associated with Arterial Stiffness in Chronic Kidney Disease.

Arterial stiffness influences the prognosis of patients with end-stage kidney disease; however, the factors that promote arterial stiffness in chronic kidney disease (CKD) patients remain unknown. We aimed to explore the clinical factors associated with arterial stiffness in CKD. Between September 2017 and September 2022, all CKD patients treated at the Department of Nephrology, General Hospital of the Chinese People's Liberation Army, excluding dialysis patients, were screened and their medical records within the last month were collected. Arterial stiffness was measured by the augmentation index (AIx). The correlative clinical factors with arterial stiffness were explored in different linear regression models. 559 patients were included in the study. AIx@75 increased as the deterioration of CKDG1-CKDG5, with values of 1 (-9, 11), 5.5 (-4, 13.25), 9 (0, 16), 12 (1.5, 23.5), and 22 (13, 28), respectively (Z = 63.03, p < 0.001). Multivariate linear regression analysis showed that AIx@75 was positively associated with female sex (β = 8.926, 95% confidence interval (CI) 6.291, 11.562, p < 0.001), age (β = 0. 485, 95% CI 0.39, 0.58, p < 0.001), mean arterial pressure (MAP) (β = 0.255, 95% CI 0.159, 0.35, p < 0.001), and was negatively associated with ACEI/ARB (β = -4.466, 95% CI -6.963, -1.969, p < 0.001) and glucocorticoid (β = -3.163, 95% CI -6.143, -0.183, p = 0.038). Smoking, eGFR, hemoglobin, and cause of disease were associated with AIx@75 in multivariate linear regression models when considering factors partly. Female, age, smoking, MAP, eGFR, cause of disease, ACEI/ARB, and glucocorticoid were found to be associated with atherosclerosis in CKD patients.

Beneficial effects of pentoxifylline in the evolution of subclinical atherosclerosis in chronic kidney disease patients

Background and Aims : Chronic kidney disease (CKD) patients present increased cardiovascular (CV) morbidity and mortality, with atherosclerosis being the underlying phenomenon in most of CV events. Clinical trials and metanalyses have linked administration of pentoxifylline (PTX) with renoprotection secondary to anti-inflammatory and antifibrotic effects in CKD patients, together with increased levels of the anti-aging protein Klotho. However, the effect of PTX on atherosclerosis in CKD patients has not been analysed.

Value of 2 risk prediction models in predicting the risk of atherosclerosis in patients with chronic kidney disease.

Cardiovascular disease (CVD) remains a high morbidity in patients with chronic kidney disease (CKD), and atherosclerosis (AS) is the main pathological basis of CVD. Atherosclerotic cardiovascular disease (ASCVD) is one of the major complications and causes of death in CKD patients. Monitoring and paying attention to the risk of AS is the manifestation of multidisciplinary comprehensive treatment. Through continuous monitoring the risk factors of AS, patients with high AS risk can be detected early, and then risk factors can be treated to improve the prognosis and life quality of CKD patients and reduce the CVD mortality of CKD. The Framingham risk prediction model and Chinese 10-year ASCVD risk prediction model can comprehensively evaluate the AS risk. The predictive value of the 2 risk prediction models has been widely confirmed in the general population, but the application in CKD population needs to be further explored. Thus, the aim of this study is to analyze the value of the 2 risk prediction models in predicting AS risk of CKD population and to find a simple and reliable method to predict AS risk of CKD population. This study was a cross-sectional study and 146 CKD patients (CKD group) and 14 healthy controls (control group) were recruited. Carotid ultrasound examination was performed to measure the intima-media thickness of left and right carotid arteries to evaluate the prevalence of AS. Medical history, physical examination, and clinical laboratory test data were collected to calculate Framingham Risk Score (FRS) and ASCVD score for all participants. We compared baseline data and AS positive rate between the CKD group and the control group. The AS positive rates detected by FRS, ASCVD score, and carotid ultrasound examination were compared in terms of Kappa consistency test, authenticity, reliability, and benefits. There were no significant differences in sex, age, and BMI between the CKD group and the control group (all P>0.05). The levels of systolic blood pressure, diastolic blood pressure, pulse pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, blood urea nitrogen, serum creatinine, and glycosylated hemoglobin in the CKD group were significantly higher than those in the control group (all P<0.05), while high density lipoprotein cholesterol and glomerular filtration rate were significantly lower than those in the control group (both P<0.05). The positive rates of AS in the CKD group detected by FRS, ASCVD score, and carotid ultrasound examination (43.84%, 53.42%, and 46.58%, respectively) were all significant higher than those in the control group (all P<0.01). There was no significant difference in the positive rate of AS in the CKD group among the 3 methods (P=0.24). The AS positive rate detected by FRS was highly consistent with ASCVD score (Kappa value was 0.647, P<0.001), FRS was moderately consistent with carotid ultrasound examination (Kappa value was 0.447, P<0.001), and ASCVD score was consistent with carotid ultrasound examination (Kappa value was 0.373, P<0.001). The sensitivities of FRS and ASCVD score were 67.65% and 73.53%, respectively, the specificities were 76.92% and 64.10%, respectively. The sensitivity was 91.44% and specificity was 49.31% when FRS and ASCVD score were used in parallel. And the sensitivity was 49.74% and the specificity was 91.71% when FRS and ASCVD score were used in series. The positive rates of AS in CKD patients detected by risk prediction models are not different from that detected by carotid artery ultrasound, and there are good consistency and coincidence rate among risk prediction models and carotid artery ultrasound. Risk prediction models are suitable for predicting the risk of AS in patients with CKD, and the combined application of them can further improve the sensitivity or specificity of diagnosis.

Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease.

Chronic kidney disease (CKD) occurrence is rising all over the world. Its presence is associated with an increased risk of premature death from cardiovascular disease (CVD). Several explanations of this link have been put forward. It is known that in renal failure, an array of metabolites cannot be excreted, and they accumulate in the organism. Among them, some are metabolites of tryptophan (TRP), such as indoxyl sulfate and kynurenine. Scientists have become interested in them in the context of inducing vascular damage in the course of chronic kidney impairment. Experimental evidence suggests the involvement of TRP metabolites in the progression of chronic kidney disease and atherosclerosis separately and point to oxidative stress generation as one of the main mechanisms that is responsible for worsening those states. Since it is known that blood levels of those metabolites increase significantly in renal failure and that they generate reactive oxygen species (ROS), which lead to endothelial injury, it is reasonable to suspect that products of TRP metabolism are the missing link in frequently occurring atherosclerosis in CKD patients. This review focuses on reports that shed a light on TRP metabolites as contributing factors to vascular damage in the progression of impaired kidney function.

Interleukin-6 gene polymorhisms and interleukin-6 levels are associated with atherosclerosis in CKD patients.

Inflammation is a major risk factor for atherosclerosis. Genetic polymorphisms in the inflammatory cytokine genes have been associated with atherosclerosis. Because levels of inflammatory cytokines are markedly elevated in patients with chronic kidney disease (CKD), we hypothesized that genotypic variations in the interleukin-6 (IL-6) gene are a cause of systemic inflammatory states and atherosclerosis in South African CKD patients. 120 CKD patients and 40 healthy controls were included. Serum IL-6 and high-sensitivity C-reactive protein (hs-CRP) levels were measured. Functional polymorphisms in the IL-6 genes were genotyped using polymerase chain reaction-sequence specific primer (PCR-SSP) methods. Carotid intima-media thickness (CIMT) and the presence of plaque were assessed by B-mode ultrasonography. Serum IL-6 and hs-CRP levels were increased in patients with CKD compared with healthy controls (p < 0.001). In CKD patients, serum IL-6 above the median value was associated with carotid plaque (OR: 2.11; 95% CI: 1.74-2.57, p=0.004), with excess risk confined to the group with high IL-6 levels. Significant associations were found between the IL-6 gene and atherosclerosis in the CKD group (for G/G genotype: OR=1.21, 95% CI=1.05-1.39, p=0.012; for GG+GC vs. CC: OR=1.14, 95% CI=1.02-1.28, p=0.035). Patients with GG+GC genotype of the IL-6 gene polymorphism had higher levels of IL-6 than those with CC genotype (p=0.029). In South African CKD patients, the IL-6 gene promoter polymorphism is associated with high serum IL-6 levels and atherosclerosis. The relationship between atherosclerosis and -174G/C polymorphism in the IL-6 gene suggests that IL-6 may be a potential pro-inflammatory mediator of atherosclerosis in CKD patients.

SUN-268 SURFACTANT PROTEIN-D (SP-D) GENE POLYMORPHISM INFLUENCES THE RISK OF ATHEROSCLEROSIS IN BLACK SOUTH AFRICAN CKD PATIENTS

Atherosclerosis is increasingly being recognised as a polygenic disease where complex interactions between genetic and environmental factors play an important role. Because chronic low-grade inflammation is common to both chronic kidney disease (CKD) and cardiovascular disease (CVD), we hypothesized that inflammatory genetic markers would enhance the susceptibility for atherosclerosis in CKD patients. In this study, we evaluated a cohort of CKD patients for different genes of importance for inflammation that individually have shown a correlation to atherosclerosis. A total of 120 CKD patients and 40 healthy controls were enrolled. Five polymorphisms in three different genes were analysed: myeloperoxidase (MPO) – 129G/A and – 463G/A, surfactant protein D (SP-D) SP-D Met11Thr and SP-D Thr160Ala, and regulated upon normal T-cell expressed and secreted (CCL5) – 403G/A. Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasonography. The SP-D Thr160Ala (OR, 3.19) and CCL5– 403 (OR, 1.40) polymorphisms were significantly commoner among the CKD patients compared to the controls (Table 1). At CIMT evaluation, 71 patients (57.3%) had subclinical atherosclerosis. The SP-D Thr160Ala polymorphism was significantly associated with atherosclerosis (OR, 3.08; 95% CI: 1.07–8.87, p=0.037), and this relationship remained after adjustment for age, gender, smoking and cholesterol and mean arterial blood pressure. No associations were found for MPO – 129G/A, MPO– 463G/A, SP-D Met11Thr and CCL5 (Table 2). Table 1Genotype frequenciesPolymorphismsNumber of participantsCKD patientsControlsP valueMPO -129GGGACKD=120, controls=39118 (98.3%)2 (1.7%)39 (100%)0 (0%)0.568MPO - 463GGGA or AACKD=120, controls=3946 (38.3%)74 (61.7%)16 (41.0%)23 (69.0%0.765SP-D Met11ThrCCCT or TTCKD=120, controls=399 (7.5%)111 (92.5%)8 (20.5%)31 (79.5%)0.022SP-D 160 Thr160AlaGGAG or AACKD=120, controls=4099 (82.5%)21 (17.5%)38 (95%)2 (5%)0.038CCL5 - 403GGGA or AACKD=114, controls=3818 (15.8%)96 (84.2%)0 (0%)38 (100%)0.009 Open table in a new tab Table 2Association between candidate gene polymorphisms and atherosclerosisPolymorphismOdds ratio (95% confidence interval)P valueMPO – 129GG versus GA1.40 (0.09 – 21.86)0.810MPO -463GG versus GA/AA1.19 (0.90 – 1.57)0.228SP-D Met11ThrCC versus CT/TT0.96 (0.86 – 1.07)0.410SP-D 160 Thr160AlaGG versus AG/AA2.20 (1.00 – 4.91)0.048CCL5GG versus GA/AA1.02 (0.87 – 1.20)0.826 Open table in a new tab In this study, carriers of SP-D Thr160Ala genotype were more susceptible to atherosclerosis. The data support previous observations that SP-D plays a role in the aetiology of atherosclerotic disease development. Therefore, the SP-D 160 Thr160Ala genotype might perhaps be useful as biomarker in predicting atherosclerosis susceptibility.

Prevalence and progression of subclinical atherosclerosis in patients with chronic kidney disease and diabetes

Background and aimsCardiovascular disease is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD) and diabetes. Traditional cardiovascular risk factors fail to fully account for the increase in cardiovascular risk in these patients. This study aims to analyse the prevalence and progression of subclinical atherosclerosis in CKD patients with and without diabetes. MethodsWe included data from CKD patients with and without diabetes free from previous cardiovascular events from the NEFRONA cohort. Patients underwent baseline and 24-month follow-up carotid and femoral ultrasound examinations. Multivariable models were used to assess the contribution of diabetes to the presence and plaque progression. ResultsA total of 419 patients with diabetes and 1129 without diabetes were included. Diabetic patients were older, had higher BMIs, more hypertension and dyslipidaemia. At baseline, the proportion of patients with plaque was higher among diabetic patients (81.4% vs. 64.1%, p < 0.001). Diabetic patients more frequently had more than two vascular territories with plaque (64.4% vs. 48.4%, p < 0.001). Multivariable analysis indicated that plaque at baseline was significantly associated with age, gender, smoking and renal replacement therapy (RRT) in the non-diabetic patients, but only with age and male gender in diabetic patients. Plaque progression was significantly associated with age, number of territories with basal plaque, smoking and RRT in both groups. ConclusionsSubclinical atherosclerosis is more prevalent, carries a higher plaque burden and is more rapidly progressive in renal patients with diabetes. In these patients, diabetes outweighs other described risk factors associated with the presence of subclinical atherosclerosis.

The Relationship between Carotid and Femoral Artery Intima-Media Thickness and Histopathologic Grade of Atherosclerosis in Patients with Chronic Kidney Disease

Background/Aims: Variability in the grade of atherosclerosis among patients with chronic kidney disease (CKD) could affect the ultrasound measurements of intima media thickness (IMT). We sought to investigate IMTs of carotid (cIMT) and femoral (fIMT) arteries in CKD patients and assess the degree of their correlation with histopathological atherosclerosis. Methods: Eighty-nine out of 99 enrolled subjects completed this study. The subjects were divided into 3 groups: 34 patients with CKD (Case group), 31 with coronary artery disease undergoing coronary artery bypass graft (CABG, positive control group), and 24 healthy kidney donors (negative control group). For histopathological assessment of atherosclerosis, arterial tissue samples were obtained from the patients in each study group. The cIMT and fIMTs were measured by ultrasonography. Results: Histopathological atherosclerosis was present in 82.3, 100, and 20.8% of CKD, CABG, and donor groups respectively (p < 0.001). CKD patients had higher values of cIMT and fIMT than the donor group (p = 0.01 and 0.004, respectively). cIMT was positively correlated with the grade of atherosclerosis in the CKD group only (p < 0.001), while fIMT was correlated with the grade of atherosclerosis in both CKD and donor groups (p < 0.001 and p = 0.009 respectively). In CKD patients, cIMT >0.65 mm and femoral values >0.57 mm predicted the presence of histopathological atherosclerosis with sensitivities of 96 and 92% respectively. Conclusion: Higher values of cIMT and fIMT in CKD patients are associated with higher rates and degrees of histopathological atherosclerosis. Additionally, when compared to fIMT, cIMT has a higher sensitivity for detecting atherosclerosis in CKD patients.

Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury.

Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL-mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients.

Brain natriuretic peptide as a potential novel marker of salt-sensitivity in chronic kidney disease patients without cardiac dysfunction.

Although the renin-angiotensin system (RAS) is counter-balanced by a salt-sensitive mechanism in the hypertensive state, both are reported to be up-regulated in chronic kidney disease (CKD) patients. We conducted this study to evaluate the associations among the RAS, renal function, hypertension, and atherosclerosis, as well as to identify markers for salt-sensitivity. A total of 213 pre-dialysis CKD patients with preserved cardiac function (EF >50%) were enrolled. Their renal and cardiac biochemical markers and plasma renin activity (PRA) were measured, and echocardiography and carotid artery ultrasound were performed. Their salt intake was estimated by the NaCl excretion from a 24-h collected urine sample. The PRA was higher in patients with hypertension (p=0.018), and had a significant negative correlation with the eGFR (r=-0.23, p=0.0067). Importantly, the PRA had a strong negative correlation with the brain natriuretic peptide (BNP) level (r=-0.28, p=0.017) regardless of whether the patients were being treated with RAS inhibitors. The BNP level was related to the renal functions (eGFR: p=0.001, ACR: p=0.009). There was a significant positive correlation between the BNP level and carotid intima-media thickness (p<0.001). A multivariate analysis revealed that older age and an excess of NaCl excretion were independent predictors of BNP elevation (p=0.02 and 0.003, respectively). Our analysis revealed details of the counterbalance between BNP and PRA, as well as identifying that excess salt intake is a predictor of BNP elevation. These results indicate that the BNP could be a possible valuable marker for salt sensitivity, and that high salt sensitivity could facilitate atherosclerosis in CKD patients.

Early markers of cardiovascular risk in chronic kidney disease

Background: Patients with chronic kidney disease (CKD) present a markedly increased cardiovascular (CV) morbidity and mortality since the early stages and have a high prevalence of accelerated atherosclerosis, inflammation and endothelial dysfunction. Nontraditional cardiovascular risk factors and serum cardiac biomarkers would contribute to explain this increased morbidity. Aim: The aim is to investigate the relation among serum cardiac biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP), cardiac troponin T (cTnT), nontraditional cardiovascular risk factors (serum uric acid, homocysteine), inflammatory indexes (C-reactive protein (CRP) serum ferritin, fibrinogen) and noninvasive predictors of atherosclerosis (carotid intima-media thickness (cIMT), brachial artery flow mediated dilation (baFMD), and left ventricular mass index (LVMI)) in CKD patients. Materials and methods: In 50 patients with CKD in stage 2/3 kidney disease outcomes quality initiative (KDOQI) and 18 age- and sex-matched healthy controls, the following parameters were measured: cardiac markers (cTnT and NT-proBNP), renal function, inflammatory markers (CRP, serum ferritin and fibrinogen), serum uric acid and homocysteine. We have also evaluated LVMIs, cIMT and baFMD. Results: In our study, we showed an increase of NT-proBNP and the serum cTnT, of serum uric acid and homocysteine with a positive correlation with the increase of cIMT and LVMI and reduced baFMD compared with the controls. Conclusions: Serum cardiac biomarkers and nontraditional cardiovascular risk factors increase already in the stage 2/3 KDOQI contributing to explain the high cardiovascular morbidity and mortality of these patients. The NT-proBNP seems to have a rise earlier compared with serum cTnT; however, both seemed to be a useful clinical biomarker for evaluating noninvasive predictors of atherosclerosis in CKD patients.

Suppressed soluble Fms–like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease

Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.

Hypertriglyceridemic Waist is Associated with Increased Carotid Atherosclerosis in Chronic Kidney Disease Patients

Background: Patients with chronic kidney disease (CKD) have an unacceptably high risk of death, primarily as a result of cardiovascular disease (CVD). The ‘hypertriglyceridemic waist' phenotype has been proposed as a simple and strong predictor of CVD risk. Therefore, we investigated the relationship between the hypertriglyceridemic waist phenotype and carotid atherosclerosis in CKD patients. Methods: In a cross-sectional study, we enrolled 785 prevalent CKD patients [416 males, aged 44.6 years (21.7-69.4), glomerular filtration rate 52.5 ml/min/1.73 m² (5.3-119.4)]. We divided the patients into three groups: group 1: waist circumference >90 cm in men or >85 cm in women and triglycerides ≥2 mmol/l (n = 109); group 3: waist circumference ≤90 cm in men or ≤85 cm in women and triglycerides <2 mmol/l (n = 379), and group 2: the remaining patients (n = 297). Routine biochemical parameters and carotid artery intima-media thickness (IMT) were measured. Results: The prevalence of the hypertriglyceridemic waist phenotypes was 13.8% in the CKD patients. Triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol concentrations in group 1 were significantly higher than those in group 3. Carotid artery IMT of the hypertriglyceridemic waist group was the highest. Conclusion: The hypertriglyceridemic waist phenotype was associated with worse carotid atherosclerosis in CKD patients. This suggests that the hypertriglyceridemic waist phenotype may be useful for predicting CVD risk in CKD patients.

Endothelial dysfunction, inflammation and atherosclerosis in chronic kidney disease – a cross-sectional study of predialysis, dialysis and kidney-transplantation patients

BackgroundCardiovascular morbidity and mortality are high in chronic kidney disease (CKD) patients compared to the general population. Systemic inflammation may contribute to endothelial dysfunction and accelerated atherosclerosis in CKD patients. We assessed the relationship among, endothelial dysfunction, early atherosclerosis and inflammation in predialysis, dialysis and post kidney-transplantation CKD patients. Methods and resultsWe studied 76 consecutive CKD patients; 38 predialysis, 18 haemodialysis and 22 kidney-transplant patients. A group of 65 age and gender matched controls were also studied. In both patients and controls, high-sensitivity C-reactive protein (CRP) levels, systemic endothelial function (brachial artery flow mediated dilation, FMD,%) and carotid artery intima-media thickness (IMT, mm) were measured.CKD patients had increased CRP levels (3.7 [1.0–6.0]mg/L vs 1.0 [0.5–2.1]mg/L; p<0.001), reduced FMD (2.2 [1.0–4.0] vs 5.6 [4.4–7.1]; p<0.001) and increased IMT (0.82±0.21 vs 0.67±0.16; p<0.001) values compared to controls. In CKD patients, a significant negative correlation was found between CRP levels and FMD responses (r=−0.51; p<0.001) while a significant positive correlation was found between CRP and IMT values (r=0.50; p<0.001). Increased CRP levels were an independent predictor of both abnormal FMD and IMT after adjusting for age, systolic and diastolic BP and total cholesterol.Compared with predialysis and kidney-transplant patients, haemodialysis subjects had significantly lower FMD and higher CRP and IMT values. ConclusionsCKD patients taken together have a higher inflammatory status compared to controls. Abnormal FMD responses and IMT values are more commonly found in dialysis patients. Our findings suggest that endothelial dysfunction and atherosclerotic changes correlate with inflammation.

Kynurenine pathway – a new link between endothelial dysfunction and carotid atherosclerosis in chronic kidney disease patients

The endothelium dysfunction is an important component of atherosclertic cardiovascular disease. It has been also suggested that kynurenine pathway activation may be involved in the pathogenesis of this disease. This is a cross-sectional study in chronic kidney disease (CKD) patients (n=106; 60 Males). The plasma markers of endothelial dysfunction and kynurenine (KYN), 3-hydroxykynurenine (3-HKYN), kynurenic acid (KYNA), anthranilic acid (AA) and quinolinic acid (QA) were measured in relation to an early indicator of the systemic atherosclerosis - intima-media thickness (IMT). Kynurenines, von Willebrand factor (vWF), thrombomodulin (TM), soluble adhesion molecules (sICAM-1, sVCAM-1) and IMT in each uraemic group were significantly higher than in healthy people. In contrast, no significant differences in sE-selectin and sP-selectin concentrations were observed between CKD patients and controls. Kynurenines were positively associated with vWF, TM, sICAM-1 and sVCAM-1, whereas sP-selectin was inversely associated with the most of kynurenines. IMT was positively correlated both with kynurenines: KYN, 3-HKYN, QA as well as with endothelial markers: TM, vWF, sICAM-1 and sVCAM-1 (all p<0.01). Finally, multiple regression analysis identified age, vWF, sVCAM-1 and QA levels as the independent variables significantly associated with increased IMT in this population (adjusted r² = 0.51). This study suggests a relationship between kynurenine pathway activation, endothelial dysfunction and the progression of atherosclerosis in CKD patients. It opens a new idea that the inhibition of kynurenine pathway may provide an effective strategy to slow down endothelial dysfunction and thereby the prevalence of atherosclerosis in this population.

Circulating Matrix Metalloproteinase-2 Is an Independent Correlate of Proteinuria in Patients with Chronic Kidney Disease

Background/Aim:Matrix metalloproteinase-2 (MMP-2) has been implicated in chronic kidney disease (CKD) and cardiovascular disease. However, there is no knowledge about the correlations between serum levels of MMP-2, proteinuria and atherosclerosis in patients with CKD. We investigated whether serum MMP-2 levels were associated with proteinuria, intima media thickness (IMT), and the presence of carotid atherosclerotic plaque in CKD patients. Methods: CKD patients without hemodialysis (n = 99) were enrolled. MMP-2 levels were measured by an ELISA system. IMT and carotid atherosclerotic plaque were evaluated by a high-resolution ultrasonography. Results: Multivariate analyses revealed that low-density lipoprotein (p < 0.001), MMP-2 (p = 0.001) and systolic blood pressure (p = 0.011) were independent correlates of proteinuria. Age- and serum creatinine-adjusted MMP-2 levels were significantly increased (p = 0.001) in proportion to the increasing levels of proteinuria. Further, age (p < 0.001), systolic blood pressure (p = 0.015) and MMP-2 levels (p = 0.042) were independent correlates of IMT. MMP-2 levels were significantly (p < 0.01) higher in patients with atherosclerotic plaque than those without it. Conclusions: The present study demonstrated that serum levels of MMP-2 were one of the independent correlates of proteinuria and IMT in patients with CKD. Our results suggest that serum MMP-2 levels may be one of the risk factors for renal damage and atherosclerosis in CKD patients.

Guest editorial: hypertension and kidney disease

Guest editorial: hypertension and kidney disease