Endotoxemia is Related to Systemic Inflammation and Atherosclerosis in Peritoneal Dialysis Patients

Szeto, Cheuk‐Chun; Kwan, Bonnie Ching‐Ha; Chow, Kai‐Ming; Lai, Ka-Bik; Chung, Kwok-Yi; Leung, Chi‐Bon; Li, Philip Kam-Tao

doi:10.2215/cjn.03600807

Cited by 188 publications

(170 citation statements)

References 37 publications

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“…This is in keeping with the only previous report (in PD patients) (21). There was a lack of association with hsCRP in the patient group as a whole, in contrast to the association in HD patients (with a generally higher degree of systemic inflammation).…”

Section: Discussionsupporting

confidence: 91%

Circulating Endotoxemia

McIntyre

Harrison

Eldehni

et al. 2011

Clinical Journal of the American Society of Nephrology

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406

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SummaryBackground and objectives Translocated endotoxin derived from intestinal bacteria has a wide range of adverse effects on cardiovascular (CV) structure and function, driving systemic inflammation, atherosclerosis and oxidative stress. This study's aim was to investigate endotoxemia across the spectrum of chronic kidney disease (CKD).Design, setting, participants, & measurements Circulating endotoxin was measured in 249 patients comprising CKD stage 3 to 5 and a comparator cohort of hypertensive patients without significant renal impairment. Patients underwent extended CV assessment, including pulse wave velocity and vascular calcification. Hemodialysis (HD) patients also received detailed echocardiographic-based intradialytic assessments. Patients were followed up for 1 year to assess survival. ResultsCirculating endotoxemia was most notable in those with the highest CV disease burden (increasing with CKD stage), and a sharp increase was observed after initiation of HD. In HD patients, predialysis endotoxin correlated with dialysis-induced hemodynamic stress (ultrafiltration volume, relative hypotension), myocardial stunning, serum cardiac troponin T, and high-sensitivity C-reactive protein. Endotoxemia was associated with risk of mortality.Conclusions CKD patients are characteristically exposed to significant endotoxemia. In particular, HD-induced systemic circulatory stress and recurrent regional ischemia may lead to increased endotoxin translocation from the gut. Resultant endotoxemia is associated with systemic inflammation, markers of malnutrition, cardiac injury, and reduced survival. This represents a crucial missing link in understanding the pathophysiology of the grossly elevated CV disease risk in CKD patients, highlighting the potential toxicity of conventional HD and providing a novel set of potential therapeutic strategies to reduce CV mortality in CKD patients.

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Section: Discussionsupporting

confidence: 91%

Circulating Endotoxemia

McIntyre

Harrison

Eldehni

et al. 2011

Clinical Journal of the American Society of Nephrology

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406

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“…Interestingly, we noted higher levels of endotoxin in patients with eGFR.60 ml/min per 1.73 m 2 . Previous studies have reported elevated or unchanged endotoxin levels in patients with more advanced CKD (7,(26)(27)(28)(29). This apparent discrepancy may be explained by several factors.…”

Section: Discussionmentioning

confidence: 86%

“…The Bruneck Study showed that elevated plasma levels of endotoxin are associated with CVD in the general population (6). Endotoxemia has also been shown to be related to inflammation and atherosclerosis in peritoneal dialysis patients (7). However, the effect of subclinical endotoxemia in patients with CKD has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD

Poesen

Ramezani

Claes

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives CD14 plays a key role in the innate immunity as pattern-recognition receptor of endotoxin. Higher levels of soluble CD14 (sCD14) are associated with overall mortality in hemodialysis patients. The influence of kidney function on plasma sCD14 levels and its relationship with adverse outcomes in patients with CKD not yet on dialysis is unknown. This study examines the associations between plasma levels of sCD14 and endotoxin with adverse outcomes in patients with CKD.Design, setting, participants, & measurements We measured plasma levels of sCD14 and endotoxin in 495 Leuven Mild-to-Moderate CKD Study participants. Mild-to-moderate CKD was defined as presence of kidney damage or eGFR,60 ml/min per 1.73 m 2 for $3 months, with exclusion of patients on RRT. Study participants were enrolled between November 2005 and September 2006.Results Plasma sCD14 was negatively associated with eGFR (r=-0.34, P,0.001). During a median follow-up of 54 (interquartile range, 23-58) months, 53 patients died. Plasma sCD14 was predictive of mortality, even after adjustment for renal function, Framingham risk factors, markers of mineral bone metabolism, and nutritional and inflammatory parameters (hazard ratio [HR] per SD higher of 1.90; 95% confidence interval [95% CI],1.32 to 2.74; P,0.001). After adjustment for the same risk factors, plasma sCD14 was also a predictor of cardiovascular disease (HR, 1.30; 95% CI, 1.00 to 1.69; P=0.05). Although plasma sCD14 was associated with progression of CKD, defined as reaching ESRD or doubling of serum creatinine in models adjusted for CKD-specific risk factors (HR, 1.24; 95% CI, 1.01 to 1.52; P=0.04), significance was lost when adjusted for proteinuria (HR, 1.19; 95% CI, 0.96 to 1.48; P=0.11). There was neither correlation between plasma endotoxin and sCD14 (r=-0.06, P=0.20) nor was endotoxin independently associated with adverse outcome during follow-up.Conclusions Plasma sCD14 is elevated in patients with decreased kidney function and associated with mortality and cardiovascular disease in patients with CKD not yet on dialysis.

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“…Disruption of the epithelial barrier structure and function in turn amplifies local and systemic inflammation by allowing translocation of bacterial toxins and other noxious products into the intestinal wall and systemic circulation. Indeed, inflammation in the CKD population is frequently associated with endotoxemia without signs of clinical infection [13,14], and recent papers highlight bacterial translocation and its association with systemic inflammation in end-stage renal disease (ESRD) patients maintained on hemodialysis [15,16]. Serum pro-inflammatory cytokine levels (IL-1, TNF-a, IL-6, IL-13) and circulating endotoxin are significantly associated with increased mortality in hemodialysis patients [17][18][19], and systemic inflammation is strongly associated with comorbidities including cardiovascular disease, anemia, and malnutrition [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

et al. 2014

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Background Gut inflammation is prevalent in chronic kidney disease (CKD) and likely contributes to systemic inflammation via disruption of the epithelial tight junction with subsequent endotoxin and bacterial translocation. Aims To study the expression profile of inflammatory and tight junction proteins in the colon from CKD rats compared to healthy controls, and demonstrate the role of Nrf2 (transcription factor nuclear factor erythroid 2-related factor 2) using a potent Nrf2 activator. Methods CKD was induced via 5/6 nephrectomy in Sprague-Dawley rats, and dh404 (2 mg/kg/day) was used to study the effects of systemic Nrf2 activation. The experimental groups included sham, CKD and CKD? dh404 rats. Blood and colon tissues were analyzed after a 10-week study period. Results Colon from CKD rats showed histological evidence of colitis, depletion of epithelial tight junction proteins, significant reduction of Nrf2 and its measured target gene products (NQO1, catalase, and CuZn SOD), activation of NFkB, and upregulation of pro-inflammatory molecules (COX-2, MCP-1, iNOS, and gp91 phox ). Treatment with dh404 attenuated colonic inflammation, restored Nrf2 activity and levels of NQO1, catalase and CuZn SOD, decreased NFkB and lowered expression of COX-2, MCP-1, iNOS, and gp91 phox . This was associated with restoration of colonic epithelial tight junction proteins (occludin and claudin-1). Conclusions CKD rats exhibited colitis, disruption of colonic epithelial tight junction, activation of inflammatory mediators, and impairment of Nrf2 pathway. Treatment with an Nrf2 activator restored Nrf2 activity, attenuated colonic inflammation, and restored epithelial tight junction proteins.

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Endotoxemia is Related to Systemic Inflammation and Atherosclerosis in Peritoneal Dialysis Patients

Cited by 188 publications

References 37 publications

Circulating Endotoxemia

Circulating Endotoxemia

Associations of Soluble CD14 and Endotoxin with Mortality, Cardiovascular Disease, and Progression of Kidney Disease among Patients with CKD

Role of Nrf2 Dysfunction in Uremia-Associated Intestinal Inflammation and Epithelial Barrier Disruption

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