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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Background. Chronic renal replacement therapy patients exhibit reduction in skeletal muscle function as a result of a combination of metabolic effects and muscle fibre size reduction. The aim of this study was to compare muscle mass with function in patients with chronic kidney disease (CKD) at stages 4 and 5 on haemodialysis (HD) and peritoneal dialysis (PD), and investigate the associations of muscle wasting in a cross-sectional cohort. Methods. We studied 134 patients (60 HD, 28 PD and 46 CKD 4). The three groups were well matched for age, sex, diabetes and dialysis vintage. Cross-sectional area (CSA) of muscle and fat was measured from a standardized multi-slice CT scan of a 6 cm long section of thigh. CSA of soft tissue was taken from appropriate fat and muscle densities. Functional assessment was by the sit-to-stand 60 test, assessing both the number of sit-to-stands possible under controlled conditions in 60 s (STS 60), and the time taken to perform five sit-to-stand movements (STS 5). Data were collected on a wide range of potential determinants of muscle CSA. Results. There were no significant differences in haemoglobin between males or females or between any of the groups studied. Serum phosphate and calcium-phosphate product were higher in HD patients as compared to CKD4 patients, but there were no differences in these variables when comparing PD patients with either CKD4 or HD patients. Muscle CSA correlated well with objective functional assessments in males (STS 60 R ¼ 0.52, P<0.0001) and females (R ¼ 0.41, P ¼ 0.004), and STS performance was reduced in dialysed patients as compared with CKD 4. Univariate analysis demonstrated that muscle CSA was associated with serum albumin concentration (R ¼ 0.49, P<0.0001), age (R ¼ À0.35, P ¼ 0.005) and C-reactive protein (R ¼ À0.34, P ¼ 0.004). Creatinine clearance, dialysis adequacy, dialysis vintage and time-averaged serum bicarbonate, calcium and phosphate concentrations were not correlated with muscle CSA. Conclusion. In conclusion, patients with dialysis-treated CKD 5 exhibited more functionally significant muscle wasting than patients with CKD 4. This may be amenable to modification with targeted exercise or amelioration of factors associated with observed differences in muscle mass.

This study has successfully utilized a novel technique for the quantification of calcification. We have demonstrated vascular calcification and associated cardiovascular dysfunction in CKD 4, PD and HD with significant differences between the groups. Thirty percent of individuals show no calcification, even those established on renal replacement therapy for a prolonged period of time. Further work is required to identify factors which promote progression of arterial calcification in those who are susceptible.

Plasma PPi is negatively associated with vascular calcification in end-stage renal disease (ESRD) and CKD but is not affected by dialysis, the mode of dialysis or nutritional or inflammatory status. Although these data are consistent with an inhibitory effect of PPi on vascular calcification, further studies are needed to establish a causal role.