.
Objective. The lifespan of dialysis patients is as short as in patients with metastatic cancer disease, mainly due to cardiovascular disease (CVD). DNA methylation is an important cellular ...mechanism modulating gene expression associated with ageing, inflammation and atherosclerotic processes.
Design. DNA methylation was analysed in peripheral blood leucocytes from three different groups of chronic kidney disease (CKD) populations (37 CKD stages 3 and 4 patients, 98 CKD stage 5 patients and 20 prevalent haemodialysis patients). Thirty‐six healthy subjects served as controls. Clinical characteristics (diabetes mellitus, nutritional status and presence of clinical CVD), inflammation and oxidative stress biomarkers, homocysteine and global DNA methylation in peripheral blood leucocytes (defined as HpaII/MspI ratio by the Luminometric Methylation Assay method) were evaluated. CKD stage 5 patients (n = 98) starting dialysis treatment were followed for a period of 36 ± 2 months.
Results. Inflamed patients had lower ratios of HpaII/MspI, indicating global DNA hypermethylation. Analysis by the Cox regression model demonstrated that DNA hypermethylation (HpaII/MspI ratio <median) was significantly associated with both all‐cause (RR 5.0; 95% CI: 1.7–14.8; P < 0.01) and cardiovascular (RR 13.9; 95% CI: 1.8–109.3; P < 0.05) mortality, even following the adjustment for age, CVD, diabetes mellitus and inflammation.
Conclusion. The present study demonstrates that global DNA hypermethylation is associated with inflammation and increased mortality in CKD.
Chromosome segregation depends on sister chromatid cohesion which is established by cohesin during DNA replication. Cohesive cohesin complexes become acetylated to prevent their precocious release by ...WAPL before cells have reached mitosis. To obtain insight into how DNA replication, cohesion establishment and cohesin acetylation are coordinated, we analysed the interaction partners of 55 human proteins implicated in these processes by mass spectrometry. This proteomic screen revealed that on chromatin the cohesin acetyltransferase ESCO2 associates with the MCM2‐7 subcomplex of the replicative Cdc45‐MCM‐GINS helicase. The analysis of ESCO2 mutants defective in MCM binding indicates that these interactions are required for proper recruitment of ESCO2 to chromatin, cohesin acetylation during DNA replication, and centromeric cohesion. We propose that MCM binding enables ESCO2 to travel with replisomes to acetylate cohesive cohesin complexes in the vicinity of replication forks so that these complexes can be protected from precocious release by WAPL. Our results also indicate that ESCO1 and ESCO2 have distinct functions in maintaining cohesion between chromosome arms and centromeres, respectively.
Synopsis
Binding of the DNA replication helicase MCM to ESCO2 enables the acetyltransferase to acetylate cohesin complexes on nascent DNA. This modification protects cohesin from precocious release by WAPL and is required for maintenance of sister chromatid cohesion at centromeres.
ESCO2 is recruited to chromatin by MCM.
ESCO2‐MCM interactions are important for cohesin acetylation on nascent chromatin and centromeric cohesion.
ESCO1 and ESCO2 maintain cohesion between chromosome arms and centromeres, respectively.
Recruitment of cohesin acetyltransferase ESCO2 by the MCM2‐7 replication complex to chromatin is required for cohesin acetylation around replication forks to maintain centromeric cohesion.
Background. Endothelial dysfunction (ED) is common in patients with moderate to advanced chronic kidney disease (CKD). Recently, visfatin, a protein with insulin-mimetic properties, was shown to be ...associated with sVCAM-1. Thus, we hypothesised that visfatin may be a marker of ED in CKD. Methods. We studied 406 patients with different stages of non-diabetic CKD (50% males, 46 ± 12 years), testing the relationship between flow-mediated dilatation (FMD), assessed by high resolution brachial ultrasonography, and plasma adiponectin and visfatin concentrations. Eighty healthy volunteers (50% males, 46 ± 11 years) served as matched controls. Results. Compared to healthy controls, ED was observed in all stages of CKD (Stages 1–5) and correlated strongly with the reduction in estimated glomerular filtration rate (eGFR). Whereas visfatin concentrations were found to be increased in all but CKD stages 1 and 2, adiponectin levels were found to be increased in all patients but CKD stage 1. Visfatin and adiponectin levels were strongly correlated with eGFR (rho = −0.62 and rho = −0.72, respectively, P < 0.001 for both). FMD levels were negatively correlated with both visfatin and adiponectin levels (rho = −0.53 and, rho = −0.57, respectively, P < 0.001 for both). In a multiple regression model, eGFR levels (Beta = 0.74, P < 0.001), visfatin (Beta = −0.15, P < 0.001), age (Beta = 0.06, P < 0.01), adiponectin (Beta = 0.09, P < 0.05), HOMA-IR (Beta = 0.07, P < 0.05) and hsCRP (Beta = −0.08, P < 0.05) were all found to be significantly related to FMD. Conclusions. We conclude that the circulating levels of visfatin and adiponectin are associated with ED in all stages of CKD, independently of inflammation and insulin resistance.
Objective. The role of obesity in promoting or preventing the complications of haemodialysis patients remains unclear, with several studies suggesting that obesity may even be beneficial. We tested ...the hypothesis that abdominal fat deposition in HD patients is a risk factor associated with both increased inflammation and protein–energy wasting (PEW), as well as elevated mortality risk. Methods. A cross-sectional study with mortality follow-up median 41 (interquartile range 25–47) months of haemodialysis patients n = 173, 100 men, aged 65 (51–74) years. Abdominal fat deposition was assessed by means of a conicity index (Ci), which estimates fat accumulation in the abdomen as the deviation of body shape from a cylindrical towards a double-cone shape (i.e. two cones with a common base at the waist level). The Ci was studied with regard to baseline inflammatory, anthropometric and nutritional markers, including subjective global assessment (SGA). Results. Across increasing tertiles of the Ci, patients were older, fatter and more inflamed (P < 0.01 for all). At the same time, they presented a higher prevalence of PEW (SGA >1), reduced handgrip strength and lower S-creatinine (P < 0.01 for all). An increased abdominal fat deposition was associated with worse outcome independently of age, sex, comorbidities and dialysis vintage Cox HR 1.93 (95% CI = 1.06–3.49), but the predictive value disappeared following adjustment for interleukin-6 (IL-6) and PEW. Conclusion. Abdominal fat deposition in haemodialysis patients is linked to both inflammation and PEW, resulting in an increased mortality risk. Our results support the idea that regional differences in adiposity accumulation may have diverse implications on patient outcome.
In the present study, we explore the role of decreased renal function and a genetic polymorphism on the recently discovered protein resistin, apparently able to inhibit hepatic insulin action in ...mice. We also investigate possible links with inflammation and the insulin resistance present in patients with chronic kidney disease (CKD). This is a post hoc, cross-sectional study comparing 239 prevalent CKD patients with varying degrees of renal function impairment with an age- and gender-matched randomly selected control group of 25 individuals. Glomerular filtration rate (GFR) was estimated by the mean of urea and creatinine clearance (24-h urine samples) (n=204) or by iohexol clearance (n=60). Plasma analysis of blood lipids, insulin, glucose, inflammatory markers (high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-α, vascular cellular adhesion molecule, intercellular adhesion molecule) and resistin (kit from LINCO Research, St Charles, MS) was performed using commercially available assays or routine methods. Insulin resistance was estimated by quantitative insulin-sensitivity check index (QUICKI) and homeostasis model assessment for insulin resistance (HOMA-IR) and body composition by dual-energy X-ray absorptiometry. Genotyping of a C/G promoter single nucleotide polymorphism (n=168) at position -180 of the resistin gene was performed by PyroSequencing™. Serum levels of resistin were markedly elevated in the CKD patients with both advanced (39.9±1.3 ng/ml) and mild to moderate (23.2±1.0 ng/ml) renal function impairment, as compared to controls (8.5±0.7 ng/ml; P<0.001). In a multiple linear regression model in patients (adjusted r2=0.60), only GFR (β=3.4; P<0.0001), lean body mass (β=2.2; P<0.001) and the inflammatory markers were independently associated with circulating resistin levels. There was a weak but significant impact of -180 C/G genotype on plasma levels of resistin (median 43.0±2.4 ng/ml in CC, 37.5±2.0 ng/ml in CG, and 41.1±4.9 ng/ml in GG; P<0.05). Univariate analysis of non-diabetic patients and controls showed that serum resistin was associated with markers of glucose metabolism. However, in a multiple regression model, resistin, as well as all the measured markers of inflammation, was only associated with insulin resistance if GFR was not taken into account. Circulating resistin levels are strongly associated with both GFR and inflammatory biomarkers in CKD. As the significant relationship between plasma resistin levels and insulin resistance was lost following the correction for GFR, resistin is not a likely mediator of insulin resistance in patients with CKD. Renal function is an important factor to take into account in clinical studies relating insulin sensitivity to inflammatory biomarkers in CKD as well as in patients with diabetes mellitus, who often have an impaired renal function.
While dysmetabolism is common in patients with chronic kidney disease (CKD) and associated with mortality, the mechanisms mediating these changes are unclear. New data implicate fibroblast growth ...factor (FGF)-19 as a possible entero-hepatic modulator of lipid metabolism.
Using samples previously gathered as part of a randomized placebo-controlled study of antioxidative therapy for postprandial dysmetabolism, we investigated short-term (4 h) postprandial changes in circulating FGF-19 (ELISA) and the relationship to metabolic markers in six haemodialysis (HD) patients and nine matched healthy subjects (HS), with each participant assessed on four separate occasions.
The postprandial FGF-19 response was blunted in patients maximum change +34.63 (0.24-186) pg/mL versus controls maximum change +150.3 (31.2-378.7) pg/mL; P < 0.0001, and the area under the curve (AUC; pg × min × mL(-1)) was also significantly lower 18 019 (12 513-44 387) versus 38 517 (19 775-72 816; P < 0.01). In patients, we found univariate correlations between AUC FGF-19 with AUC C-peptide (rho = 0.71; P = 0.001), AUC insulin (rho = 0.63; P = 0.001), but not with AUCs for triglycerides (TG) or glucose. Finally, treatment with the antioxidative compounds N-acetyl cysteine or MP865, but not with placebo, was associated with higher plasma FGF-19 (NAC and MP865 coefficients -0.28 and -0.23, P < 0.05, respectively).
In advanced CKD, the postprandial FGF-19 response appears to be blunted, with partial normalization following antioxidative treatments. A blunted FGF-19 response was associated with impaired insulin and C-peptide signalling.
. Carrero JJ, Qureshi AR, Axelsson J, Yilmaz MI, Rehnmark S, Witt MR, Bárány P, Heimbürger O, Suliman ME, Alvestrand A, Lindholm B, Stenvinkel P (Karolinska Institutet, Stockholm; and Karo Bio AB, ...Novum, Huddinge; Sweden). Clinical and biochemical implications of low thyroid hormone levels (total and free forms) in euthyroid patients with chronic kidney disease. J Intern Med 2007; 262: 690–701.
Objectives. In this study, we explore the associations of decreased thyroid hormone levels with inflammation, wasting and survival in biochemically euthyroid patients with end‐stage renal disease (ESRD).
Design. After exclusion of 23 patients with thyroid‐stimulating hormone (TSH) values outside the normal range (0.1–4.5 mIU L−1), 187 clinically and biochemically euthyroid incident ESRD stage 5 patients starting dialysis were followed for a median of 20 (range 1–60) months. Measurements of total and free forms of thyroid hormones, s‐albumin, hs‐CRP, interleukin (IL)‐6, vascular adhesion molecule (VCAM)‐1 and insulin‐like growth factor 1 (IGF‐1) were performed at baseline.
Results. In this population, 17 out of 210 patients (8%) were defined as subclinically hypothyroid. Multivariate analysis, according to receiver operating characteristic (ROC) curves, showed that mortality was best predicted by total triiodothyronine (T3). When using the cut‐off levels derived from ROC, low T3 levels were associated with increased inflammation (higher hs‐CRP, IL‐6 and VCAM‐1) and lower concentration of both s‐albumin and IGF‐1. Finally, low T3 but not low free triiodothyronine was associated with worse all‐cause (Likelihood ratio = 45.4; P < 0.0001) and cardiovascular mortality (Likelihood ratio = 47.8; P < 0.0001) after adjustment for confounding factors.
Conclusion. This study showed that low T3 levels are independent predictors of all‐cause and also cardiovascular disease mortality in biochemically euthyroid patients, perhaps due to an intimate association with inflammation. Based on these results, the use of T3 levels in studies assessing the relationship between thyroid dysfunction and mortality risk is recommended.
Serum albumin is a widely used biomarker of nutritional status in patients with CKD; however, its usefulness is debated. This study investigated serum albumin and its correlation with several markers ...of nutritional status in incident and prevalent dialysis patients.
In a cross sectional study, serum albumin (bromocresol purple), and other biochemical (serum creatinine), clinical (subjective global assessment SGA), anthropometric (handgrip strength, skinfold thicknesses), and densitometric (dual energy x-ray absorptiometry) markers of nutritional status were assessed in 458 incident (61% male; mean age 54 +/- 13 years; GFR, 6.6 +/-2.3 ml/min per 1.73 m(2); recruited 1994–2010) and 383 prevalent (56% male; mean age 62 +/- 14 years; recruited 1989–2004) dialysis patients.
In incident patients: serum albumin was correlated with sex (beta = -0.13; P = 0.02), diabetes mellitus (beta = -0.18; P = 0.004), and urinary albumin excretion (beta = -0.42; P = 0.001) but less so with poor nutritional status (SGA score >1; beta = -0.19; P = 0.001). In prevalent patients, serum albumin was correlated with age (beta = -0.14; P = 0.05), high-sensitivity C-reactive protein (beta = -0.34; P = 0.001), diabetes mellitus (beta = -0.11; P = 0.04), and SGA score >1 (beta = -0.14; P = 0.003). In predicting nutritional status assessed by SGA and other markers, adding serum albumin to models that included age, sex, diabetes, and cardiovascular disease did not significantly increase explanatory power.
In incident and prevalent dialysis patients,serum albumin correlates poorly with several markers of nutritional status. Thus, its value as a reliable marker of nutritional status in patients with ESRD is limited. In addition, the following inconsistencies between the main text and Tables 1 and 3 are also corrected as follows. (1) In Table 1, the GFR initially written as 6 +/- 3 ml/min per 1.73(2) should be corrected to 6.6 +/- 2.3 ml/min per 1.73(2). (2) On line 11 of page 1448, under the Clinical Correlates of Serum Albumin Concentration section describing the multiple regression models (Table 3), the P value was initially written as“serum albumin was associated with age (beta = -0.14; P = 0.05).” The P value should be corrected to have the same value as that given in Table 3 (beta = -0.14; P = 0.005. corrected.
The high risk of cardiovascular disease (CVD) and premature death in patients with CKD associates with a plethora of elevated circulating biomarkers that may reflect distinct signaling pathways or ...simply, are epiphenomena of CKD. We compared the predictive strength of 12 biomarkers analyzed concomitantly in patients with stage 5 CKD.
From 1994 to 2014, 543 patients with stage 5 CKD (median age =56 years old; 63% men; 199 patients had CVD) took part in our study on malnutrition, inflammation, and CVD in incident dialysis patients. Circulating levels of albumin, ferritin, high-sensitivity C-reactive protein (hsCRP), IGF-1, IL-6, orosomucoid, troponin T (TnT), TNF, soluble intracellular adhesion molecule, soluble vascular cellular adhesion molecule 1 (sVCAM-1), and platelet and white blood cell (WBC) counts were analyzed as predictors of the presence of clinically overt CVD at baseline, protein-energy wasting (PEW), and subsequent all-cause mortality. During follow-up for a median of 28 months, there were 149 deaths, 81 of which were caused by CVD.
Most biomarkers were elevated compared with reference values and--except for albumin, ferritin, and IGF-1-higher in patients with CVD. In receiver operating characteristic analysis, age, IL-6, TnT, hsCRP, and IGF-1 were classifiers of baseline CVD and predictors of all-cause mortality. In addition to age, diabetes mellitus, smoking (for CVD), and PEW, only IL-6, relative risk (RR) 1.10 and 95% confidence interval (95% CI, 1.02 to 1.19), sVCAM-1 RR 1.09 (95% CI, 1.01 to 1.17), and serum albumin RR 0.89 (95% CI, 0.83 to 0.95) associated with baseline CVD, and only WBC, hazard ratio (HR) 1.94 (95% CI, 1.34 to 2.82), IL-6 HR 1.79 (95% CI, 1.20 to 2.67), and TNF HR 0.65 (95% CI, 0.44 to 0.97) predicted all-cause mortality.
In addition to age and comorbidities, only IL-6, sVCAM-1, and albumin could-independently of other biomarkers-classify clinical CVD, and only IL-6, WBC, and TNF could-independently of other biomarkers-predict all-cause mortality risk. These data underscore the robustness of IL-6 as a classifier of clinically overt CVD and predictor of all-cause mortality in patients with stage 5 CKD.
Abstract
Individuals may have a different body odor, when they are sick compared to healthy. In the non-human animal literature, olfactory cues have been shown to predict avoidance of sick ...individuals. We tested whether the mere experimental activation of the innate immune system in healthy human individuals can make an individuals’ body odor be perceived as more aversive (intense, unpleasant, and disgusting). Following an endotoxin injection (lipopolysaccharide; 0.6 ng/kg) that creates a transient systemic inflammation, individuals smelled more unpleasant compared to a placebo group (saline injection). Behavioral and chemical analyses of the body odor samples suggest that the volatile components of samples from “sick” individuals changed qualitatively rather than quantitatively. Our findings support the hypothesis that odor cues of inflammation in axillary sweat are detectable just a few hours after experimental activation of the innate immune system. As such, they may trigger behavioral avoidance, hence constituting a first line of defense against pathogens of infected conspecifics.
PDF
