Increased Intestinal Permeability to Differently Sized Polyethylene Glycols in Uremic Rats: Effects of Low- and High-Protein Diets

Magnusson, Martin; Magnusson, Karl‐Eric; Sundqvist, Tommy; Denneberg, Torsten

doi:10.1159/000186158

Cited by 70 publications

(46 citation statements)

References 18 publications

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“…20 Several previous studies have suggested a shift in the gut microbiome in CKD, 21,22 as well as altered intestinal barrier function in this setting. [23][24][25][26] Thus, it is plausible that an increased intestinal absorption of trimethylamine or hepatic synthesis of TMAO could contribute to the elevated TMAO concentrations in CKD.…”

Section: Discussionmentioning

confidence: 99%

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Stubbs

House

Ocque

et al. 2016

Journal of the American Society of Nephrology

354

334

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Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r 2 =0.31, P,0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 mM [54.8-133.0 mM] for dialysis-dependent patients versus 3.3 mM [3.1-6.0 mM] for healthy controls; P,0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min-max] 71.2 mM [29.2-189.7 mM] pretransplant versus 11.4 mM [8.9-20.2 mM] posttransplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 mM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P,0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography. Patients with CKD have a high prevalence of cardiovascular comorbidities, which primarily contributes to the exceedingly high mortality in this group. 1,2 For example, the 5-year survival for ESRD patients receiving dialysis is approximately 35%, with .50% of the mortality in this group resulting directly from cardiovascular causes. 1 It is well established that CKD patients exhibit a disproportionate burden of atherosclerosis as compared with individuals having normal kidney function. [2][3][4][5] Furthermore, a higher prevalence of traditional risk factors for the development of atherosclerosis, such as hypertension, diabetes and hyperlipidemia, only partially accounts for the accelerated atherosclerosis in CKD patients, leading to the hypothesis that unique risk factors must be present in this population. 6,7

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Section: Discussionmentioning

confidence: 99%

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Stubbs

House

Ocque

et al. 2016

Journal of the American Society of Nephrology

354

334

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“…These inflammatory changes sometimes coexisted with peptic ulcer disease and ischemic lesions [46]. Permeability of the intestinal wall in CKD rats and in CKD patients was demonstrated in the early 1990s in studies that detected appearance of orally administered PEGs of various MWs in the urine [47,48]. The intestinal environment is further altered due to low fiber/low symbiont intake in CKD patients who are advised to adhere to a low potassium, low phosphorus diet (thus decreased intake of fruit, vegetables, yogurt, dairy).…”

Section: Breakdown Of the Gut-epithelial Barrier And Systemic Translomentioning

confidence: 99%

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

et al. 2018

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In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

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“…This finding is of particular importance in view of the impaired function of the intestinal barrier in uremia. Both in uremic animals [17] and in uremic patients [18], the intestinal wall becomes leaky as documented by the penetration of polyethylene glycols of different molecular weights across the intestinal wall [17]. At least in animal experiments, escape of bacteria across the intestinal wall has been documented [19].…”

Section: The Gut Contributes To the Uremic Syndromementioning

confidence: 99%

Intestinal-Renal Syndrome: Mirage or Reality?

Ritz

2011

Blood Purif

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The recent interest in the role of the intestine in the cardiovascular stability of uremic patients, specifically on dialysis, but potentially also in chronic kidney disease, must be seen against the background of the recent great interest in the role of the gut in chronic heart failure [Curr Opin Clin Nutr Metab Care 2008;11:632–639]. There has been a long-standing interest in the role of the intestine in renal failure, mainly concerning the role of metabolites of bacterial metabolism in the gut as potential uremic toxins. This area has recently been given a new twist by the finding that increased endotoxin concentrations in the blood of dialyzed patients are associated with hypotensive episodes and myocardial ‘stunning’. Recent studies suggest that intradialytic underperfusion of myocardial areas, the so-called stunning, may be related to the entry of bacterial endotoxin and/or cytokines across the mucosal barrier into the circulation, where they have a negative impact on myocardial function (and presumably beyond the negative cardiac side effect also contribute to catabolism and malnutrition). Entry of bacterial endotoxin during dialysis sessions is presumably the result of intermittent underperfusion of the intestine if the effective blood volume is rapidly reduced causing breakdown of the mucosal barrier. Apart from the impact on myocardial perfusion, the entry of bacterial endotoxin and/or cytokines across the mucosal barrier may also contribute to malnutrition, wasting and reduced life expectancy in hemodialyzed patients. Such a causal relationship is absolutely plausible in view of an extensive literature on congestive heart failure where clinical and experimental evidence indicates that bacterial endotoxin and/or cytokines may escape from a hypoperfused edematous gut, entering the circulation, triggering an inflammatory response, upregulating circulating cytokines and interfering with the function of the heart through several pathogenic mechanisms.

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Increased Intestinal Permeability to Differently Sized Polyethylene Glycols in Uremic Rats: Effects of Low- and High-Protein Diets

Cited by 70 publications

References 18 publications

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

Intestinal-Renal Syndrome: Mirage or Reality?

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