The importance of paraoxonase 1 activity in chronic kidney disease.

Paraoxonase 1 (PON1) is one of the most significant antioxidative enzymes associated with high-density lipoprotein (HDL). It has been proved that is involved in the pathogenesis of many diseases including chronic kidney disease (CKD). The association between PON1 and CKD seems to be mutual, such that the disease produces a significant decrease in PON1 activity levels, while the genetics of PON1 may affect the risk of susceptibility to CKD. Recent studies reveal that the decrease in serum PON1 activity observed in non-dialyzed and dialyzed CKD patients as well as in renal transplant (RT) patients is linked to an increased vulnerability to atherosclerosis. We intend to summarize current literature concerning PON1 activity in CKD, highlighting on the main determinants of PON1 activity, its association with oxidative stress, the impact of its genetic polymorphism on the disease development, the effect of drugs and nutritional state. Furthermore, evidence supporting the implication of reduced PON1 activity in the incident of cardiovascular disease in CKD patients, is also examined. It appears that despite the lack of standardization of PON1 activity measurement, PON1 remains a valuable biomarker for the researchers through the last decades, which contributes to the assessment of the antioxidant status having prognostic benefit on adverse clinical outcomes at various stages and etiologies of kidney disease.

Cardiac mechanics in response to proteasome inhibition: a prospective study.

AIM: Ubiquitin-Proteasome System (UPS) is of paramount importance regarding the function of the myocardial cell. Consistently, inhibition of this system has been found to affect myocardium in experimental models; yet, the clinical impact of UPS inhibition on cardiac function has not been comprehensively examined. Our aim was to gain insight into the effect of proteasome inhibition on myocardial mechanics in humans. METHODS AND RESULTS: We prospectively evaluated 48 patients with multiple myeloma and an indication to receive carfilzomib, an irreversible proteasome inhibitor. All patients were initially evaluated and underwent echocardiography with speckle tracking analysis. Carfilzomib was administered according to Kd treatment protocol. Follow-up echocardiography was performed at the 3rd and 6th month. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells.At 3 months after treatment, we observed early left ventricular (LV) segmental dysfunction and deterioration of left atrial (LA) remodelling, which was sustained and more pronounced than that observed in a cardiotoxicity control group. At 6 months, LV and right ventricular functions were additionally attenuated (P < 0.05 for all). These changes were independent of blood pressure, endothelial function, inflammation, and cardiac injury levels. Changes in PrA were associated with changes in global longitudinal strain (GLS), segmental LV strain, and LA markers (P < 0.05 for all). Finally, baseline GLS < -18% or LA strain rate > 1.71 were associated with null hypertension events. CONCLUSION: Inhibition of the UPS induced global deterioration of cardiac function.

Prognostic and Diagnostic Value of Endocan in Kidney Diseases.

Endocan, previously called endothelial cell-specific molecule-1, is a soluble proteoglycan that is predominantly expressed in vascular endothelial cells of the lungs and kidneys. It is upregulated by proinflammatory cytokines and plays a critical role in inflammatory, proliferative, and neovascularization processes. The utility of endocan as a biomarker in a wide spectrum of diseases is being increasingly acknowledged. In this review, we summarize the current evidence concerning the role of endocan in kidney diseases, with emphasis on its prognostic and diagnostic value. It seems that the determination of plasma endocan levels may provide useful prognostic information in many types of renal failure such as chronic kidney disease, IgA nephropathy, and diabetic nephropathy. Endocan could additionally improve the early diagnostic evaluation of acute kidney disease, chronic renal allograft injury, and acute rejection after kidney transplantation, thus contributing to endothelial cell injury monitoring in a timely manner.

Serum Endocan Levels are Associated With Paraoxonase 1 Concentration in Patients With Chronic Kidney Disease.

Endocan is a soluble proteoglycan released by the vascular endothelium. The increase of its serum levels is associated with inflammation, endothelial dysfunction and cardiovascular events in patients with chronic kidney disease (CKD). We studied the association of serum endocan with the lipid profile of 105 CKD patients with dyslipidemia, divided in two groups, non-dialyzed (CKD, N = 57) and hemodialysis (HD, N = 48) in comparison with 30 normal controls (NC). We also analyzed endocan in relation with the concentration of two serum HDL-linked members of the paraoxonase (PON) family, PON1 and PON3, which have been previously found to have antiatherogenic properties. The results showed that endocan levels were significantly higher in HD patients than in CKD patients (P < 0.001) and NC (P < 0.001). PON1 was significantly decreased only in HD patients compared to NC (P < 0.001), whereas PON3 was significantly increased in both patient groups (P < 0.001). Endocan levels were significantly and positively correlated with total cholesterol and LDL-C in CKD and additionally were negatively correlated with HDL-C in HD group. PON1 levels were significantly correlated with endocan in both groups, while no correlation was observed for PON3 in either group. Multiple regression analysis between endocan and the above lipid parameters in the total of patients revealed that endocan was independently associated only with PON1 (ß = -0.513, P = 0.002). It is concluded that the increase of serum endocan levels in patients with CKD may be associated with the decrease of PON1 concentration, irrespective of lipid alterations produced by atherosclerosis development.

Association of lipid profile with serum PON1 concentration in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) are at high risk of atherosclerotic events; dyslipoproteinemia and the decrease of the HDL-linked enzyme paraoxonase 1 (PON1), might have a major role. This study intends to compare the association between lipid profile and serum PON1 levels in renal failure (RF) and hemodialysis (HD) patients. Serum lipids, HDL-subclasses and PON1 concentration were evaluated in 90 patients with CKD, divided into groups: RF (n = 46) and HD (n = 44), and in 30 normal individuals (control group). The results showed that PON1 was significantly lower in HD patients than in RF and controls (p < 0.001). In RF patients under statin therapy, PON1 did not differ from that of patients without statins. In HD patients without statins, PON1 was considerably low, whereas in HD with statins (30.42 ± 12.62 µg/mL) was lower than RF with statins (49.31 ± 14.94, p < 0.001). PON1 concentration was significantly and positively associated with HDL-C, HDL3-C and Apo A1 in all groups. Additionally, in HD patients PON1 was negatively associated with LDL-C. Multiple regression analysis revealed that LDL-C and statin treatment were independently related to PON1 concentration in HD patients (ß = -0.331, p = 0.026 and ß = 0.344, p = 0.020, respectively). In RF patients, HDL3-C and Apo A1 are strong determinants of PON1 levels. It is concluded that different parameters of lipid profile seem to affect serum PON1 concentration of RF and HD patients and probably contribute to the delay of atherosclerosis.

Serum hepcidin levels are associated with serum triglycerides and interleukin-6 concentrations in patients with end-stage renal disease.

Hepcidin has emerged as a peptide with a key role in the regulation of iron homeostasis in patients with chronic kidney disease (CKD), having a strong dependence on inflammation. Recent studies reveal that hepcidin may be also associated with the progression of atherosclerosis. This study was performed to analyze the relation of hepcidin to markers of atherosclerosis and inflammation in patients on dialysis. A total of 90 individuals were enrolled. Sixty patients with end-stage renal disease, who were on hemodialysis (HD) (N = 30) and peritoneal dialysis (N = 30) were compared with 30 normal controls (NC). Age, body mass index, time on dialysis, serum lipids, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured and analyzed in correlation with hepcidin concentration. It was found that patients on HD and peritoneal dialysis have significantly higher (P < 0.0001) levels of hepcidin, CRP and IL-6 than NC. Hepcidin in dialysis patients is significantly related to age (r = 0.373, P = 0.012), serum triglycerides (r = 0.401, P = 0.005), HDL-C (r = -0.268, P = 0.048), CRP (r = 0.436, P = 0.0007) and IL-6 (r = 0.569, P < 0.0001). In multiple regression analysis, hepcidin correlated independently with triglycerides (ß = 0.402, P = 0.041) and IL-6 (ß = 0.559, P = 0.006). Moreover, patients with high triglycerides in combination with high IL-6 levels have significantly increased concentrations of hepcidin than those with low triglycerides and low IL-6 levels (P < 0.0001). Elevated levels of hepcidin in patients with CKD on dialysis may be related to the occurrence of high triglycerides and high IL-6 serum concentrations. This probably suggests that hepcidin may play a role to the progression of atherosclerosis and inflammation, but this hypothesis should be further evaluated.

Lipid abnormalities and oxidized LDL in chronic kidney disease patients on hemodialysis and peritoneal dialysis.

Dyslipoproteinemia and oxidative modification of low-density lipoprotein (oxLDL) contribute to the development of oxidative stress and atherosclerosis in chronic kidney disease (CKD). On the contrary, high-density lipoprotein cholesterol (HDL-C), especially HDL3-C subtype, has protective effect against oxidative damage. There is limited evidence referring HDL-C subclass levels in patients on dialysis. This study was designed to compare lipid abnormalities and oxLDL levels in hemodialysis (HD) and peritoneal dialysis (PD) patients. Serum lipids, HDL subclasses, and oxLDL were measured in 55 patients with CKD-stage 5 (31 patients on HD and 24 patients on PD) and in 21 normal controls (NC). The results showed that in dialysis patients, triglycerides were higher than in controls (p < 0.0001) and HDL-C was significantly lower (p < 0.0001). The HDL2-C subclass concentration did not differ significantly between patients and controls, while HDL3-C was lower in patients (11 ± 0.5 mg/dL) than in NC (23 ± 1, p < 0.0001). oxLDL levels were markedly increased in patients (1.92 ± 0.29 mg/L) compared to NC (0.22 ± 0.05, p < 0.0001). Patients on PD had higher levels of cholesterol (p < 0.001) and apolipoprotein B (p < 0.05) than patients on HD. However, HDL-C, HDL-C subclasses, and oxLDL concentrations did not differ significantly between PD and HD patients. It is concluded that patients with CKD have a nearly 10-fold elevation of oxLDL compared with NC. Patients on PD have differences in the lipid profile compared with patients on HD; however, both modalities seem to possess similar potential to atherosclerosis development.

Patients with duodenal ulcer have lower levels of serum cholesterol compared to other dyspeptic patients independently of Helicobacter pylori status.

OBJECTIVE: The association between Helicobacter pylori (H. pylori) infection and serum lipid profile is still controversial. The aim of this study was to determine any possible relationship between H. pylori infection and the lipid profile of patients with upper gastrointestinal symptoms. MATERIAL AND METHODS: Consecutively selected 20-70 year-old dyspeptic patients who had undergone esophagogastroduodenoscopy were evaluated for H. pylori infection using both the CLO test and Giemsa staining. Serum total cholesterol (C), HDL-C, LDL-C, apo-A1, apo-B and triglyceride levels were measured. RESULTS: A total of 137 patients (median age 52.0 years) were studied. Total cholesterol levels were lower in H. pylori-infected patients than in H. pylori-negative patients (mean +/- SEM: 199.3 +/- 5.9 versus 212.6 +/- 4.6 mg/dl, p = 0.08). Patients with duodenal ulcer (DU) had significantly lower levels of all measured lipidemic parameters including cholesterol, with the exception of triglycerides, in comparison with either H. pylori-positive or -negative dyspeptic patients (cholesterol: 177.6 +/- 6.5 versus 214.6 +/- 4.2 mg/dl, p < 0.0001). However, there was no difference in the total cholesterol/HDL-C ratio between DU patients and the rest of the dyspeptic patients. CONCLUSIONS: Among H. pylori-positive and H. pylori-negative patients there was no difference in lipid profile apart from a trend towards total cholesterol levels being lower in H. pylori-positive patients. However, cholesterol, HDL-C, LDL-C, apo-A and apo-B were all decreased in DU patients even though this reduction did not result in a fall in the total cholesterol/HDL-C ratio. The etiologic factor differentiating the lipid profiles among dyspeptics only in H. pylori-positive patients carrying a DU could be dietetic, microbial, genetic or a combination of all three.

Relationship of serum cystatin C with C-reactive protein and apolipoprotein A1 in patients on hemodialysis.

Cystatin C is considered an indicator of acute renal failure and also a risk factor of cardiovascular disease. This study was undertaken to examine the relationship of serum cystatin C with C-reactive protein (CRP), lipids, and lipid-related compounds in patients on hemodialysis (HD). Cystatin C, CRP, total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and apolipoprotein A1 and B were analyzed in serum of 30 patients on HD for 118 +/- 18 months with low-flux dialyzers, before and after HD. The results were compared with those obtained by 21 healthy individuals (NC). Multiple regression analysis was performed to evaluate the association of cystatin C concentration before HD with clinical and laboratory parameters. The results showed that cystatin C before HD was not associated with age, body mass index (BMI), or duration of HD. However, it was significantly correlated with creatinine (r = 0.435, p = 0.021) and albumin (r = 0.483, p = 0.009) concentrations. Moreover, a highly significant association was shown with logCRP (r = 0.692, p < 0.0001). Among the lipid and lipid-related compounds studied, a significant correlation was found between cystatin C and apolipoprotein A1 concentrations (r = 0.402, p = 0.034). None of those correlations were observed in the NC group. In conclusion, it seems that cystatin C levels before HD are related with CRP, an important inflammatory factor, and also with apolipoprotein A1, which has been proved to accelerate the atherosclerosis process. However more studies are needed to confirm these findings.

Atherosclerotic risk factors and carotid stiffness in elderly asymptomatic HD patients.

Several studies showed that carotid atherosclerosis and stiffness are independent prognostic factors of cardiovascular morbidity and mortality in the general population and in end-stage renal disease patients. However, the impact of established risk factors on carotid structural and elastic properties in non-diabetic elderly hemodialysis patients with negative history for cardiovascular disease has not been fully elucidated. In this paper, we investigated the effect of established and potential risk factors on carotid atherosclerosis and stiffness. Thirty stable, non-symptomatic, non-diabetic patients, aged 65-years and older (mean age 71.4+/-4.15, range 65-79) on hemodialysis for more than 6 months, were included. All patients underwent B-mode ultrasonography of common carotid artery estimating intima-media wall thickness and wall-to-lumen ratio bilaterally and checking for the presence of plaques. Carotid elasticity was evaluated by compliance, distensibility, and the incremental elastic modulus (Einc), whereas systemic arterial stiffening was evaluated by the augmentation index provided by tonometry of radial artery. Our results showed that presence of carotid plaques and wall thickening were frequent findings in this population (76% and 73.3%, respectively) and they were positively associated with fibrinogen (P<0.005), diastolic blood pressure (P<0.004), visceral obesity (P<0.001) and bio-intact PTH (i-PTH) (P=0.03). Overall, systemic and carotid stiffness were strongly correlated with hs-CRP (P=0.018), serum ferritin (P=0.02) with age (P=0.03), lipids (P=0.03) and i-PTH (P=0.05). In conclusion, our findings show that stiffening and atherosclerosis in non-symptomatic elderly HD patients are very common and they are related not only to hemodynamic changes (diastolic blood pressure), inflammation (hs-CRP, fibrinogen, ferritin) or metabolic dysfunction (increased i-PTH, abnormal lipid profile), but also to abnormal fat deposition (increased waist to hip ratio and waist circumference). Considering the high morbidity and mortality of elderly patients, close monitoring of these parameters could be useful to prevent cardiovascular events.

Oxidative stress markers and C-reactive protein in end-stage renal failure patients on dialysis.

OBJECTIVE: The inflammatory status is a well-documented factor influencing the development of oxidative stress in dialysis patients. This study intends to evaluate the inflammatory activity and the plasma levels of total antioxidant capacity (TAC) and lipid peroxidation products in patients on peritoneal dialysis (PD), by comparison with hemodialysis (HD) patients. PATIENTS AND METHODS: Plasma concentration of TAC, lipid peroxidation products and C-reactive protein (CRP) were measured in 24 patients on PD, 32 HD patients (pre and post treatment) and 16 normal controls (NC). RESULTS: All patients had higher levels of TAC and lipid peroxidation products than NC (p < 0.001). Patients on PD, had similar levels to patients before HD but significantly higher (p < 0.001) than those post HD. The CRP concentration was higher in HD than in PD patients (p < 0.05). The percentage of patients with CRP > 10 mg/l was 48% in HD patients and 21% in PD patients. No correlation was observed between CRP and TAC nor CRP and MDA levels. CONCLUSIONS: We conclude that although PD and HD patients show an equal susceptibility in oxidative stress, CRP levels are higher in HD patients and this is indicative of a higher degree of inflammatory activity in these patients.