Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease

Abstract

Background 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.

Results: Circulating 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.

Figure 1.

(a)Distribution of circulating endotoxin levels across the spectrum of CKD patients at baseline. Pediatric HD patients are illustrated separately (▲). (b) Association of estimated GFR and circulating endotoxin levels in nondialysis-dependent CKD patients.

Figure 2.

(a) In HD patients with intradialytic hypotension, predialysis endotoxin levels were significantly correlated with (i) inflammation; (ii) the number of myocardial stunned segments; (iii) intradialytic hypotension; and (iv) predialysis cardiac troponin T, a marker of myocardial damage. (b) Postdialysis endotoxin levels were significantly correlated with ultrafiltration volume.

Figure 3.

Unadjusted Cox proportional hazard of mortality over a 1-year period. Population is divided into quartiles of baseline circulating endotoxin level (P = 0.034).