Objective
Lipopolysaccharide or endotoxin constitutes most part of the outer portion of the cell wall in the gram negative bacteria. Sub-clinical endotoxemia could contribute to increased inflammation and mortality in hemodialysis patients. Endotoxin level and clinical effect are determined by its soluble receptor sCD14 and high density lipoprotein. We examine the hypothesis that endotoxin level correlates with mortality.
Methods
In this cohort study, endotoxin levels were measured in 306 long-term hemodialysis patients who were then followed for up to 42 months. Soluble CD14 and cytokines levels were also measured.
Results
The mean (±SD) endotoxin level was 2.31±3.10 EU/ml (min: 0.26 EU/ml, max: 22.94 EU/ml, inter-quartile range: 1.33EU/ml, median: 1.27EU/ml). Endotoxin correlated with C-reactive protein (r = 0.11, p<0.04). On multivariate logistic regression analysis, high body mass index (BMI) and low HDL cholesterol levels were associated with higher endotoxinemia (endotoxin below or above of median). In multivariable Cox regression analysis adjusted for case-mix and nutritional/inflammatory confounders, endotoxin levels in the 3rd quartile vs. 1st quartile was associated with a trend towards increased hazard ratio (HR) for death (HR 1.83, 95% confidence interval: 0.93–3.6, p=0.08).
Conclusions
In this hemodialysis cohort, we found associations between endotoxinemia and CRP, body composition and HDL. A moderately high endotoxin levels tended to correlate with increased mortality than the highest circulating endotoxin level. Additional studies are required to asses the effect of endotoxemia on mortality in dialysis population.
Cardiovascular and infectious diseases remain the most common causes of death among patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Basic science and epidemiological studies indicate that vitamin D has importance not only for cardiovascular health, but also for the immune response. Vitamin D signaling pathways regulate both innate and adaptive immunity, maintaining the associated inflammatory response within physiological limits. Levels of both the inactive as well as active form of vitamin D (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, respectively) are decreased in patients with CKD and ESRD. It is reasonable to hypothesize, therefore, that the immune dysfunction associated with vitamin D deficiency in patients with CKD and ESRD in part explains the misdirected inflammatory response and increased susceptibility to infection seen in this population. Indeed, observational studies show that vitamin D deficiency in patients with ESRD is associated with increased mortality, and treatment with vitamin D is associated with a decreased risk of infection, as well as reduced all-cause mortality. However, whether different vitamin D preparations have differential effects on physiological function and clinical outcomes is still unclear. A proper understanding of the immune regulatory function of vitamin D is important for the development of future therapeutic strategies.
Contrast-induced nephropathy is an increasing cause of acute kidney injury and is associated with significant mortality and morbidity. Future developments in this field will focus on refining the clinical significance of this complication, earlier diagnosis with biomarkers, clarifying the role for bicarbonate and iso-osmolar contrast agents as preventive strategies, and the introduction of new prophylactic techniques on the basis of an improved understanding of pathogenesis at the cellular level.
MitoNEET, a key regulatory protein in mitochondrial energy metabolism, exhibits a uniquely ligated [2Fe−2S] cluster with one histidine and three cysteines. This unique cluster has been postulated to sense the redox environment and release Fe−S cofactors under acidic pH. Reported herein is a synthetic system that shows how [2Fe−2S] clusters react with protons and rearrange their coordination geometry. The low-temperature stable, site-differentiated clusters [Fe 2 S 2 (SPh) 3 (CF 3 COO)] 2− and [Fe 2 S 2 (SPh) 3 (py)] − have been prepared via controlled protonation below −35 °C and characterized by NMR, UV−vis, and X-ray absorption spectroscopy. Both complexes exhibit anodically shifted redox potentials compared to [Fe 2 S 2 (SPh) 4 ] 2− and convert to [Fe 4 S 4 (SPh) 4 ] 2− upon warming to room temperature. The current study provides insight into how mitoNEET releases its [2Fe−2S] in response to highly tuned acidic conditions, the chemistry of which may have further implications in Fe−S biogenesis.
Metrics & MoreArticle RecommendationsC larification of the funding support has been added to indicate the awardees and/or the usage of each grant in the acknowledgment section. The original Acknowledgment reads "Financial support for this work was provided by the NSF (Grants CHE-1807845 and CHE-1854854) and NIH (Grants R15 CA213042 and GM120641-01)." With the addition, the revised Acknowledgment reads "Financial support for this work was provided by the NSF (Grants CHE-1807845 to E.K. and CHE-1854854 to J.S.) and NIH (Grants R15 CA213042 to E.K. for the maintenance of glove boxes, and GM120641-01 to J.S.)."
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