From the immunologic viewpoint, chronic kidney disease (CKD) is characterized by disorders of both the innate and adaptive systems, generating a complex and still not fully understood immune dysfunction. Markers of a chronically activated immune system are closely linked to several complications of CKD and represent powerful predictors for mortality in the CKD population. On the other hand, CKD patients respond poorly to vaccination and to challenges such as bacterial infection. Interestingly, the main causes of death in patients with CKD are cardiovascular and infectious diseases, both being pathologic processes closely linked to immune function. Therefore, accelerated tissue degeneration (as a consequence of chronic inflammation) and increased rate of sepsis (because of a poorly orchestrated immune response) represent the most important targets for interventions aiming to reduce mortality in CKD patients. Understanding the mechanisms behind the immune dysfunction that is peculiar to CKD generates a perspective to improve outcomes in this group of patients.
Chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular calcification, accelerated atherosclerosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. As a consequence, inflammation is a predictor of mortality in this group of patients. Specific causes of the activation of the immune system in CKD are largely unknown. Endotoxin (ET) release to the circulation represents a potentially important target for interventions aiming to reduce mortality in CKD patients. In this minireview, we propose that there are several potential sources of endotoxemia in CKD and that gut translocation, leading to the generation of ligands of the innate immune response, represents a potentially reversible cause. Prevention of endotoxemia, through treating foci of ET (periodontal disease, catheters, vascular access) or reducing translocation from the gut, will potentially reduce the inflammatory response.
Introduction: Uremic toxins play a pivotal role in the development of systemic complications of chronic kidney disease (CKD), which are largely mediated by the activation of the immune system. Triggers of inflammation in CKD are largely unknown and strategies aiming to reduce circulating ligands that could start the inflammatory response are potentially important. In the present study, we investigated the impact of sevelamer hydrochloride treatment in reducing endotoxemia and inflammation in a group of hemodialysis (HD) patients. Material and Methods: HD patients, who were converted from calcium carbonate treatment to sevelamer according to KDOQI guidelines, were included and prospectively followed for 6 months. Systemic inflammation was evaluated by serum ultra-high-sensitivity C-reactive protein (hsCRP) using an automated immunoturbidimetric assay. Endotoxin was measured using Limulus amebocyte lysate chromogenic endpoint assay. All the analyses were performed immediately before conversion and after 6 months of treatment. Results: After the exclusion of patients discontinuing the treatment, 20 patients (mean dialysis time 12 ± 4 months on HD, age 52 ± 2 years, 38% males, 11% diabetics) were included in the analysis. No significant changes were observed in Ca, P and PTH levels, while a reduction in cholesterol levels was seen. Plasma concentration of hsCRP and endotoxin significantly decreased after 6 months of conversion to sevelamer compared with baseline. Conclusion: We conclude that sevelamer treatment leads to a decrease in hsCRP levels, which was accompanied by a parallel decrease in endotoxemia, suggesting that endotoxemia may contribute to the systemic inflammation in HD patients, which was partially reduced by the use of sevelamer.
Background Increased vascular permeability is a characteristic feature of sepsis which, in the past, has been ascribed exclusively to a malfunction of endothelial cells. However, recently it has become evident that the endothelial glycocalyx is of considerable importance concerning various aspects of vascular physiology, e.g. the vascular barrier and inflammation. Heparan sulfate, one of its essential components is characteristically traceable in blood, in case the endothelial glycocalyx is damaged or destroyed. Methods In 15 pigs we investigated whether the administration of endotoxin from gram-negative bacteria (Escherichia coli) results in increased serum levels of heparan sulfate, signalizing a shedding of the glycocalyx. In addition, markers of inflammation (white blood cell count, platelet count, tumour necrosis factor-α and interleukin-6) were evaluated over an observation period of 6 hours. Results Serum heparan sulfate concentrations significantly increased over time in the endotoxin group and were significantly elevated in comparison to the control group 6 hours after administration of endotoxin (p < 0.001). In the endotoxin group all markers of inflammation significantly changed during the time course. Conclusions The administration of bacterial endotoxin induced a significant rise in degradation products of the endothelial glycocalyx.
Background: Renal failure is associated with activation of inflammatory response, but the mechanisms behind this observation and potential anti-inflammatory strategies are yet to be defined. Endotoxin (ET) translocation from the intestinal lumen can potentially trigger systemic inflammatory response, and ET binding represents a potential anti-inflammatory strategy in renal failure. The aim of this study was to evaluate the ET-binding capacity of sevelamer carbonate in an animal model of renal failure. Material and Methods: Rats were 5/6 nephrectomized to induce uremia (U) and sham-operated rats were allocated to receive normal chow (controls) or a diet with 3% sevelamer carbonate added (+SC) for 60 days. Tumor necrosis factor-α (TNF-α) and ET were measured in plasma on days 7, 30 and 60 in all animals. Results: Renal failure induced an inflammatory response, since TNF-α levels were undetectable in all control animals in contrast to the uremic group (3.18 ± 0.62, 2.58 ± 0.54 and 1.86 ± 0.47 pg/ml, respectively, on days 7, 30 and 60; p < 0.05 at all time points). Similarly, uremic rats presented an increase in ET levels (0.038 ± 0.007 EU/ml) when compared to sham-operated animals (0.008 ± 0.006 EU/ml; p < 0.05). During the study, TNF-α levels in U + SC rats were significantly lower compared with U-control animals (p < 0.05). Similarly, ET levels in U + SC rats were lower when compared with U-control rats (p < 0.005). Conclusion: In conclusion, induction of renal failure triggered inflammation and induced endotoxemia in this experimental model of chronic kidney disease, which were reduced by sevelamer treatment. This data suggests that sevelamer carbonate induces an anti-inflammatory effect in parallel to a reduction in ET.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.