Atherosclerosis In Uraemic Patients Research Articles

Effect of blood purification on serum miR-126 and VEGF levels in the process of atherosclerosis in uremic patients under maintenance hemodialysis

This study aims to study the influence of different blood purification approaches on the expression of miR-126 and VEGF serum levels in the development of atherosclerosis in uremic patients under maintenance hemodialysis (MHD). A total of 207 MHD patients with uremia were divided into HD (hemodialysis, n = 60), HDF (hemodiafiltration, n = 72), and HD + HP (hemodialysis + hemoperfusion, n = 75) groups based on different purification approaches. Eighty individuals who underwent physical examinations during the same period constituted the healthy controls. The serum levels of miR-126 and VEGF were examined by qRT-PCR and ELISA both before and after treatment, and the intima media thickness (IMT) value and plaque area were evaluated by color Doppler ultrasound. The serum miR-126 level was down-regulated in MHD patients compared with healthy controls, and this was negatively linked to VEGF. The post-treatment expression level of serum miR-126 in the HDF and HD + HP groups was remarkably increased, but VEGF was decreased in MHD patients, and especially significantly in the HDF group. In addition, IMT and plaque area were obviously improved in the HD group after treatment. Pearson correlation analysis showed a negative correlation of miR-126 with IMT and plaque area, but a positive association between VEGF and IMT and plaque area. miR-126 and VEGF are expected to become a valuable biomarker for monitoring the progression of atherosclerosis in uremic patients undergoing MHD.

Hyperhomocysteinemia and the presence of cardiovascular disease are associated with kynurenic acid levels and carotid atherosclerosis in patients undergoing continuous ambulatory peritoneal dialysis

IntroductionHyperhomocysteinemia and the activation of kynurenine (KYN) pathway have been reported as the factors participated in atherosclerosis in uraemic patients. The objective of this study was to verify whether hyperhomocysteinemia may be involved in atherosclerotic cardiovascular disease (CVD) in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Materials and methodsWe determined the plasma concentrations of KYN, KYNA, KYNA/KYN ratio, homocysteine (Hcy) and intima-media thickness (IMT) - an early reflection of the systemic atherosclerosis in CAPD patients both with and without CVD and healthy controls. ResultsKYNA concentrations and KYNA/KYN ratio were about 3 times higher in the patients with hyperhomocysteinemia (Hcy>15μM) compared to those with normal Hcy levels (<15μM), and they were significantly lower in CVD[+] than in CVD[−] patients in these studied groups. The presence of CVD was associated with higher Hcy levels only in the patients with Hcy>15μM. The positive association was between Hcy and KYNA, KYNA/KYN ratio in all CAPD patients and in CVD[+] patients with hyperhomocysteinemia. IMT was positively associated with Hcy levels in patients with hyperhomocysteinemia, whereas there was no relationship between IMT and KYNA concentrations in the studied groups. ConclusionsThese results showed the association between hyperhomocysteinemia and carotid atherosclerosis as well as the possible role of hyperhomocysteinemia in the activation of KYNA production in CAPD patients. The elevated KYNA levels observed in patients with hyperhomocysteinemia seem to be protective against Hcy-mediated atherosclerosis in these patients.

Clinical nutrition scores are superior for the prognosis of haemodialysis patients compared to lab markers and bioelectrical impedance

Malnutrition is closely related to inflammation and atherosclerosis in uraemic patients. There is still debate on how to quantify nutritional status in order to achieve the best prediction of mortality and hospitalization. Different methods to detect malnutrition were prospectively investigated for their prognostic impact on mortality and hospitalization of haemodialysis (HD) patients. We compared clinical nutrition scores (body mass index, BMI; subjective global assessment, SGA; malnutrition inflammation score, MIS; and nutritional risk screening, NRS) to lab parameters of protein and lipid metabolism, or bioelectrical impedance analysis (BIA) in 90 HD patients. Over a 3-year follow-up, all-cause mortality and hospitalization were evaluated using a Cox regression model. The scores SGA, NRS, MIS, serum albumin, prealbumin, transferrin and BIA were predictive of both mortality and hospitalization. Elevated CRP predicted only a significantly higher mortality. After adjustment for age, gender, dialysis vintage and diabetes status, the best prognostic parameters for mortality were the clinical nutrition scores, MIS-Index > or = 10 [HR 6.25 (2.82-13.87), P < 0.001], NRS [HR 4.24 (1.92-9.38), P < 0.001] and SGA B/C [HR 2.70 (1.14-6.41), P < 0.05]. In HD patients, serum markers of protein metabolism and BIA can be used for evaluation of the nutritional status. However, with regard to mortality and hospitalization risk, the individual clinical nutrition scores are superior compared to lab markers and BIA. To confirm malnutrition, we propose using clinical nutrition score generally or at least in the case of two malnutrition-positive parameters (lab, BIA, BMI).

Carbamylated low‐density lipoprotein induces proliferation and increases adhesion molecule expression of human coronary artery smooth muscle cells

Presence of accelerated atherosclerosis in dialysis patients cannot be entirely explained by conventional risk factors. Exposure to urea, which is elevated in patients with kidney disease, leads to the carbamylation of proteins. We investigated the effects of carbamylated low-density lipoprotein (cLDL) on human coronary artery vascular smooth muscle cells (VSMC). Native LDL (nLDL) was carbamylated with potassium cyanate. Cells were incubated with different concentrations of cLDL carbamylated at different time points. Cytotoxicity, apoptosis, proliferation (bromodeoxyuridine incorporation), expression of adhesion molecules and extracellular matrix protein synthesis were studied. Carbamylated low-density lipoprotein exposure leads to morphological alterations and presence of cellular debris. Neither nLDL nor cLDL caused apoptosis. Lactate dehydrogenase (LDH) release was not different between groups. Carbamylated low-density lipoprotein led to a striking proliferation in VSMC compared to nLDL. Carbamylated low-density lipoprotein significantly increased intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression compared to the control. The effects of cLDL on proliferation and adhesion molecule expression were dose-dependent and correlated with the degree of low-density lipoprotein carbamylation. cLDL had no effect on extracellular matrix protein synthesis. The results support the hypothesis that cLDL may contribute to the pathogenesis of atherosclerosis in uraemic patients.

The urokinase-type plasminogen activator/its soluble receptor system is independently related to carotid atherosclerosis and associated with CC-chemokines in uraemic patients

Introduction The urokinase-type plasminogen activator (uPA)/its soluble receptor (suPAR) and CC-chemokines are two systems contributing in the atherosclerosis. We try to establish whether these two systems were associated among themselves, and the significance of this potential association in relation to carotid atherosclerosis in uraemic patients. Materials and methods We determined uPA, suPAR, CC-chemokines: monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory proteins (CCL3, CCL4), regulated upon activation, normal T cell expressed and secreted (CCL5) and the intima-media thickness (IMT) values in uraemic patients on peritoneal dialysis (CAPD), haemodialysis (HD) and healthy controls. Results The values of the uPA/suPAR system, CCL2, CCL4 and IMT in the patients significantly exceeded those in controls, whereas CCL5 were lower in the patients than in the controls. CCL3 concentrations were similar in all investigated groups. CCL2, CCL4 and CCL5 were positively associated with uPA/suPAR system. CCL2 and CCL4 were associated with IMT. Multivariate analysis showed that uPA, suPAR and age were the strong independent variables linked to IMT values. Conclusions The carotid atherosclerosis is independently related to uPA/its soluble receptor system in dialysis patients. In addition, the strong positive associations existed between uPA/suPAR system and CC-chemokines suggesting that these two systems could cooperate and influence of atherosclerosis in these patients.

Inflammation is associated with carotid atherosclerosis in dialysis patients

To investigate the relationship between inflammatory processes and atherosclerosis in uraemic patients on chronic dialysis. A cross-sectional study in 138 dialysis patients (92 on haemodialysis and 46 on continuous ambulatory peritoneal dialysis). Serum C-reactive protein (CRP), IgG anti-Chlamydia pneumoniae antibodies, lipoprotein (a), fibrinogen and plasma homocysteine as well as the intima-media thickness and the number of atherosclerotic plaques of the carotid arteries (by Echo-Colour-Doppler) were measured in each patient One hundred and eight patients had at least one plaque and 26 had more than six plaques. Serum CRP was above the upper limit of the normal range (5 mg/I) in 85 of 138 patients (62%). IgG anti-Chlamydia pneumoniae antibodies were detectable in 64% of patients (high level in 24%, intermediate in 33% and low in 7%) and undetectable in the remaining 36% of patients. In a multiple regression model age (beta=0.35), serum CRP (beta=0.23), plasma homocysteine (beta=0.19), duration of dialysis (beta=0.19) and pulse pressure (beta=0.18) were independent predictors of intima-media thickness (R=0.54, P < 0.0001). Similarly, age (beta=0.33), serum CRP (beta=0.29), plasma homocysteine (beta=0.20) and serum albumin (beta=-0.18) were independent correlates of the number of atherosclerotic plaques (R = 0.55, P < 0.0001 ). Furthermore, in smokers, the interaction serum CRP-IgG anti-Chlamydia pneumoniae antibodies was the stronger independent predictor (beta=0.43, P=0.0001) of the number of atherosclerotic plaques while no such relationship (P=0.73) was found in non-smokers. In patients on chronic dialysis treatment CRP is independently associated to carotid atherosclerosis and appears at least in part to be explained by IgG anti-Chlamydia pneumoniae antibodies level. These data lend support to the hypothesis that inflammation plays a role in the pathogenesis of atherosclerosis in these patients.

Importance of Serotonergic Mechanisms in the Thrombotic Complications in Hemodialyzed Patients Treated with Erythropoietin

So far it is not clear how erythropoietin affects the anticoagulant properties of vascular endothelium in uremia. Since serotonin is also thought to play a role in the pathogenesis of thrombosis, the aim of the study was to evaluate major components of extrinsic coagulation pathway, markers of endothelial cell injury, lipoprotein (a) and peripheral serotonergic mechanisms during rHuEPO therapy in hemodialyzed patients. The study was performed on chronically hemodialyzed patients divided into two groups: with rHuEPO treatment and without rHuEPO therapy in relation to the control group. In uremic patients, thrombomodulin and von Willebrand factor, activity of factor VII, tissue factor pathway inhibitor (TFPI) activity, TFPI and tissue factor (TF) concentrations, lipoprotein (a) level were significantly higher when compared to healthy volunteers. Treatment with rHuEPO resulted in a further significant rise in markers of endothelial cell injury: thrombomodulin and von Willebrand factor and TFPI concentration. Extrinsic coagulation factors: activities of factor VII and X, TFPI activity and TF activity and concentration, lipoprotein (a) and vitronectin remained unchanged during rHuEPO therapy. Platelet serotonin content and whole blood serotonin were significantly lower in uremic patients relative to healthy volunteers and during rHuEPO treatment they increased significantly. Whole blood serotonin reached normal values. Plasma serotonin, significantly elevated in uremia, did not change during rHuEPO therapy. Serotonin uptake by uremic platelets was significantly impaired and remained unaltered during rHuEPO administration. Serotonin release by uremic platelets was also significantly depressed but a significant improvement was observed in rHuEPO-treated patients. Our data suggest that endothelial injury, TF pathway components and peripheral serotonergic system disturbances may predispose to thromboembolic complications and play a role in the pathogenesis of atherosclerosis in uremic patients, particularly treated with rHuEPO. Increase in TFPI may compensate the increase in TF in these patients.

The impact of an amino acid-based peritoneal dialysis fluid on plasma total homocysteine levels, lipid profile and body fat mass.

The caloric load from glucose-based peritoneal dialysis (PD) fluids contributes to hypertriglyceridaemia, adiposity and, as result of anorexia, protein malnutrition in PD patients. It has been suggested that replacement of a glucose-based by an amino acids-based PD fluid (AA-PDF) for one exchange per day might improve the nutritional status and lipid profile. Due to the uptake of methionine from the dialysate, however, exposure to AA-PDF might aggravate hyperhomocysteinaemia, a frequently occurring risk factor for atherosclerosis in uraemic patients. We studied the impact of a once daily exchange with 1.1% AA-PDF instead of glucose-based PD fluid for 2 months on plasma methionine and total homocysteine (tHcy) levels, lipid profile, butyrylcholinesterase (BChE) and body fat mass of seven stable PD patients. Results are expressed as mean+/-SEM. Methionine levels did not increase significantly during therapy, but tHcy levels increased substantially from 60+/-12 to 84+/-19 micromol/l after 1 month (P=0.039), and to 85+/-22 micromol/l after 2 months of AA-PDF treatment. Serum triglyceride concentration decreased from 3.0+/-0.4 mmol/l at entry to 2.6+/-0.5 mmol/l (at 1 month, P=0.041 vs baseline). Serum BChE also decreased from 6.9+/-0.4 U/ml at entry to 6.3+/-0.4 U/ml after 2 months (P=0.014). Total cholesterol concentration and cholesterol fractions did not change. The reduced exposure to glucose-based PD fluid for 2 months resulted in a 0.5 kg reduction in fat mass which was due mainly to a reduction in fat mass of the trunk region (0.3 kg, P=0.031). It is concluded that methionine-containing AA-PDF induces an increase in the plasma tHcy level. This might, potentially, offset the beneficial effects of an improved serum lipid profile and reduced fat mass on the risk of cardiovascular disease in PD patients. Lowering the methionine content of the fluid, therefore, may be required to overcome this adverse effect.

Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients

Due to the incidence of symptomatic atherosclerosis in uremic patients, hemostasis-derived cardiovascular risk factors, basal plasma concentrations of some endothelial-derived glycoproteins and desmopressin-induced variations of endothelial-derived proteins were studied in 22 uremic patients on prolonged maintenance hemodialysis with no cardiovascular antecedent. Compared to control subjects, patients had increased predialysis hemostasis-related cardiovascular risk factors: high fibrinogen, proconvertin, and type 1 plasminogen activator inhibitor plasma concentrations; low albumin values; generally low antithrombin III values but sometimes high. They had high predialysis plasma concentrations of endothelium-derived glycoproteins: von Willebrand factor, tissue-type plasminogen activator and urokinase-type plasminogen activator, which are secreted by endothelial cells, but also soluble thrombomodulin, a marker of endothelial cell injury. The desmopressin-induced release of tissue-type plasminogen activator and of von Willebrand factor were lower than in controls. High fibrinogen, type 1 plasminogen activator inhibitor and low albumin plasma concentrations may be linked to repeated acute phase reactions associated with hemodialysis. Data concerning endothelium-related proteins are concordant with the co-existence of a chronic in vivo endothelial activation and endothelial injury in uremia. This could be linked to the initiation and progression of atherosclerosis.

Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein.

Low-density lipoprotein (LDL) was in vitro carbamylated with potassium cyanate and the clearance was studied in man. A minor carbamylation of LDL decreased the clearance of LDL by 41% (94% of amino groups free) and by 18% (90% of amino groups free). When LDL was extensively carbamylated its clearance was substantially accelerated. Moreover, the clearance of LDL isolated from 14 haemodialysis patients (uremic-LDL) was studied in rabbits. Uraemic-LDL, injected into rabbits simultaneously with the LDL of a healthy control subject, was cleared more slowly than the control-LDL (difference in fractional catabolic rate -6.5%, P = 0.02). We also examined the lipid peroxidation of the carbamylated LDL by measuring the amount of thiobarbituric-acid reactive substances (TBARS) and formation of conjugated dienes during exposure of carbamylated LDL to 5 microM Cu2+. The carbamylated and native LDL had similar lipid peroxidation and propensity for oxidation. In summary, both the uraemic-LDL and minimally carbamylated LDL had a decreased clearance in vivo, which may contribute to the accelerated atherosclerosis in uraemic patients.

Decreased clearance of low-density lipoprotein in patients with chronic renal failure

The clearance of low-density lipoprotein (LDL) isolated from uremic patients (autologous-LDL) and from a control subject (control-LDL) was studied in 12 uremic patients on conservative management and compared to the LDL clearance in control subjects. The clearances of autologous-LDL and control-LDL were almost the same in the patients. However, the fractional catabolic rate (FCR) of the autologous-LDL (0.307 +/- 0.094 pools/day, mean +/- SD) and the control-LDL (0.289 +/- 0.081 pools/day) were significantly lower (P < 0.05 and P < 0.01, respectively) than the FCR for LDL in the control subjects (0.376 +/- 0.045 pools/day). Moreover, one-half of the patients had an abnormally low LDL clearance rate ranging from 0.146 to 0.282 pools/day. The FCR for the autologous-LDL varied from 0.146 to 0.416 pools/day between the patients and was negatively related (r = -0.68, P = 0.02) to the serum urea concentration (from 11.8 to 39.2 mmol/liter) and tended to correlate positively with the glomerular filtration values (from 9.2 to 48.3 ml/min/1.73 m2; r = 0.57, P = 0.096, non-linear relationship). In conclusion, the clearance of LDL in patients with advanced uremia on conservative management is frequently decreased. This alteration in the metabolism of the most atherogenic particle in plasma may contribute to the accelerated atherosclerosis in uremic patients.

Is there a treatment necessity for lipid disorders of uremic patients?

In the present review, the role of lipid disturbances is evaluated as a risk factor in the pathogenesis and the potential acceleration of atherosclerosis in uremic patients undergoing long-term hemodialysis. The alteration in high density lipoprotein composition with a decrease in high density lipoprotein cholesterol but a normal apoprotein AI content may have relevance to the atherogenetic process. Moreover, the accumulation of cholesterol-rich, very low density lipoproteins and intermediate density lipoproteins may play a major role in atherosclerosis since these degradation products of triglyceride-rich particles are considered as atherogenic. The hypothesis should be tested whether a correction of the abnormal catabolism of triglyceride-rich lipoproteins in uremic patients leads to a decrease in ischemic vascular events.

Effects of dietary acetate and bicarbonate on experimental atherosclerosis in rabbits

Chronic hemodialysis, using acetate-containing dialysate, may accelerate the development of atherosclerosis in uremic patients. To assess the effect of acetate on plasma lipid levels and development of atherosclerosis, rabbits and rats were fed cholesterol-free semipurified atherogenic, Zn ++-supplemented diets containing either 10% sodium acetate or sodium bicarbonate. Rabbit plasma cholesterol gradually increased during the 8-month study (58–485 mg/100 ml) but there was no significant difference between the acetate-fed and control groups. After 8 months, all rabbits had some degree of aortic intimal change. The changes involved a mean of 10% of the total aortic area. This involvement is much smaller than those previously reported and there was no significant difference between the acetate-fed rabbits and the control groups. Rabbit mortality was low (25%) and the mean weight increased from 1.7 to 2.7 kg. It is concluded that dietary acetate does not affect the rate and degree of development of hyperlipidemia and atherosclerosis. Furthermore, supplemental dietary Zn ++ may have been responsible for the low rabbit mortality rate, weight gain and possibly the retarded development of atherosclerosis.