Nutrition, inflammation and oxidative stress - CKD 1-5

Abstract

Introduction and Aims: According to the modern tendencies, the important formation factors of cardiovascular calcification in chronic kidney disease (CKD) are oxidative stress (OS) and chronic inflammation. However, the role of the indicated processes in mechanisms of cardiac valve calcification (CVC) in patients under the predialysis period of CKD were not asserted enough. In this conditions, it is also reasonable to research the functional activity of endothelium, especially of nitric oxide (NO) system, since endothelial dysfunction is one of the key mechanisms, which mediated inflammatory effects on the cardiac valve apparatus. The purpose of the current study was (1) to determine the role of activation of free radical oxidation of lipids and systemic inflammation in mechanisms of valve calcification in predialysis CKD patients, and (2) to establish in CVC group the relationship between the inflammatory markers and NO system state. Methods: We enrolled 167 (male/female, 78/89; age, 48.7 {+/-} 13.2 years; eGFR-MDRD, 51.0 {+/-} 28.2 ml/min per 1.73 m2) predialysis (stage I: 8.4%, stage II: 28.1%, stage III: 38.9%, stage IV: 18.0%, stage V: 6.6%) CKD patients. All subjects underwent echocardiographical examination for detection of valve calcification. Plasma content of malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) activities, ceruloplasmin (CP) and glutathione (GSH) concentrations as indices of pro/antioxidant system were determined using the standard methods. Inflammatory markers were performed by evaluating the serum levels of C-reactive protein (CRP) (immunoturbidimetric method), fibrinogen (gravimetric analysis) and circulating immune complexes (CICs) (polyethylene glycol precipitation test). Plasma content of nitrites (NO2-) (Green L.C. et al., 1982) was measured as marker of NO system activity. Data are presented as mean {+/-} SD. Used nonparametric statistics methods: Mann-Whitney U- test in order to compare indices in two groups, Spearman's rank R correlations for establishment of presence and strength of the relationship between the research parameters. Results: CVC was detected in 28.7% of predialysis CKD patients: isolated calcification of mitral valve - in 6.0%, aortal valve - in 7.2%, both valves - in 15.6%. In CVC group indices of MDA (p < 0.001), CP (p < 0.001), CRP (p < 0.001), fibrinogen (p = 0.005), CICs (p = 0.010) were higher, and SOD (p < 0.001), CAT (p = 0.061), GSH (p = 0.005) - lower compared to the group without calcification. Predialysis CKD patients with valve calcification had lower content of NO2- (0.053 {+/-} 0.016 vs. 0.070 {+/-} 0.016 mmol/L, Z = 4.999, p < 0.001) than subjects without calcification. For the first time it was established that in CVC group (n = p;48) NO2- level was correlated with CRP (R = -0.565, p < 0.001), fibrinogen (R = -0.415, p = 0.003) and CICs (R = - 0.512, p < 0.001) concentrations. Conclusions: (1) CVC in predialysis? CKD patients is combined with the development of OS and systemic inflammation. (2) Valve calcification under the predialysis period of CKD is characterized by the reduced content of stable metabolite of NO - NO2-, which in turn is closely related with the inflammatory parameters. (3) Availability of complex of metabolic disturbances in predialysis patients with CVC points towards the necessity of the search of means with normalizing influence on the level of lipid peroxidation, antioxidant defense, inflammatory processes and NO system state for prevention and treatment of the indicated cardiac damages. Introduction and Aims: The GNRI is a very simple and objective method to assess nutritional condition, utilizing only three objective parameters: body weight, height and serum albumin values. To date, there have been few longitudinal studies that have used GNRI to predict mortality in chronic hemodialysis patients. In the present study, we validated whether using GNRI as a nutritional screening tool could be a clinical predictor of mortality in Korean hemodialysis patients. Methods: We examined the GNRI of 120 maintenance hemodialysis patients and followed these patients for 120 months. Predictors for all-cause death were examined using life table analysis and the Cox proportional hazards model Results: Life table analysis revealed that subjects with a GNRI; < 90 (n = 19) had a marginally lower survival rate than did those with a GNRI = 90 (n = 101) (Wilcoxon test, P = 0.048). Multivariate Cox proportional hazards analyses demonstrated that the GNRI was a significant predictor of mortality [hazard ratio (HR) 0.966, 95% confidence interval (CI) 0.945-0.995, P = 0.018], after adjusting for age, sex, presence of type 2 diabetes mellitus, and body weight Conclusions: These results demonstrate that the GNRI may be a significant predictor of mortality in Korean hemodialysis patients. View this table: GFS238TB1500400GFS238TB1 Table 1 Clinical characteristics of 120 chronic hemodialysis patients according to GNRI View this table: GFS238TB2500400GFS238TB2 Table 2. Multivariate Cox proportional hazards analysis of mortality GFS238F1"> WIDTH=200 HEIGHT=195 SRC="/small/gfs23801.gif" ALT="Figure 1"> View larger version (19K): GFS238F1590629GFS238F1 Figure 1. GNRI and 120-month survival of hemodialysis patients. Subjects with a GNRI; < 90 had a lower survival rate during the follow-up period compared with that of those with a GNRI [≥] 90 (life table analysis). Introduction and Aims: Cardiovascular events are the main cause of death in patients with chronic kidney disease (CKD). Lipoproteins play an important role in the regulation of vascular integrity. Recent evidence suggests that urea-driven carbamylation of lysine residues may affect the functional properties of lipoproteins, however the effect on endothelial function is unkown. We therefore examined the effect of carbamylated low density lipoprotein (cLDL) on endothelial function. Methods: LDL from healthy donors was isolated by sequential ultracentrifugation. LDL was carbamylated ex vivo using potassium cyanate. The degree of carbamylation and oxidation was assessed by HPLC/ESI-MS/MS and TBARS assay, respectively. Vascular reactivity after treatment with native (nLDL) or carbamylated (cLDL) LDL was examined in organ chamber experiments using aortic rings of wildtype or lectin-like oxidized LDL receptor-1 (LOX-1) transgenic mice. Superoxide and nitric oxide production in aortic rings and human aortic endothelial cells (HAEC) was determined using electron spin resonance (ESR) spectroscopy. Activation of endothelial NO synthase (eNOS) was assessed by western blot techniques. In HAEC, silencing of LOX-1 was performed using LOX-1 specific siRNA. Results: Carbamylation of LDL resulted in carbamyl-Lysine levels comparable to those in patients with CKD without relevant oxidation. cLDL impaired endothelial-dependent relaxation of aortic rings, whereas nLDL had no effect. Addition of superoxide dismutase/catalase could restore vascular relaxation after cLDL treatment, indicating an important role of superoxide production in cLDL mediated endothelial dysfunction. Indeed, cLDL directly induced superoxide production in aortic rings and HAEC by uncoupled eNOS. Interestingly, cLDL mediated endothelial dysfunction was enhanced in LOX-1 transgenic mice, revealing LOX-1 as receptor for cLDL. Accordingly, siRNA-mediated knockdown of LOX-1 in HAEC could improve endothelial NO production and attenuate superoxide release. Conclusions: Our data demonstrate for the first time that carbamylated LDL, as it occurs in patients with CKD, induces endothelial dysfunction by increasing endothelial superoxide production via LOX-1. This indicates a new important mechanism which may contribute to the high cardiovascular burden of these patients. Introduction and Aims: Leptin, an adipocyte -derived hormone, is significantly elevated in CKD patients, due to its reduced renal clearance. Conflicting data exist about the relation of high levels of leptin, an appetite reducing hormone, to protein- energy wasting and, more importantly, to outcomes in CKD patients. This study was undertaken to examine a) the relation of serum leptin to the nutritional-inflammatory status and b) the way this adipokine can impact on survival in a cohort of CKD patients. Methods: Forty-seven hemodialysis (HD) and 27 peritoneal dialysis (PD) patients, after completion of baseline assessment, including body mass index (BMI), lean mass body index (LMBI) and fat mass index (FMI), serum albumin, transferrin, prealbumin, C - reactive protein (CRP), high density lipoprotein (HDL) and leptin, were follow-up for all-cause mortality. Leptin levels were examined as dichotomous variable comparing the lowest sex-specific tertile of leptin ( < 5.1 for men and; < 14.9 ng/ml for women) to the higher (middle and highest) tertiles. Results: Median leptin levels (in ng/ml) were higher in women than in men (21.3 vs. 7.2; p = 0.001), as they were also higher in PD compared to HD patients (23.0 vs. 10.7; p = 0.009). The mean values of all anthropometric parameters measured were higher and the mean duration of renal replacement therapy (57 vs. 83 months; p = 0.032) was shorter in the high leptin group compared to the low leptin group. There were no differences in age distribution, diabetes and baseline cardiovascular disease (CVD) proportions between the two groups. In the whole group, the FMI-adjusted leptin correlated positively with transferrin (r = 0.438; p = 0.001) and HDL (r = 0.255; p = 0.030) and inversely with CRP (R = -260; p = 0.026). In multiple regression analysis (R2= 0.46; p = 0.000), FMI, gender (women), dialysis mode (PD), prealbumin and transferrin were identified as independent positive predictors of leptin levels. During a median follow-up period of 50 months, 18 deaths occurred. Patients in the low leptin group had increased all-cause mortality [crude hazard ratio: 2.95 (95% CI, 1.17-7.50)], as compared to the high leptin group. Thi