Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

Gut Microbiota as a Source of Uremic Toxins

Uremic retention solutes are the compounds that accumulate in the blood when kidney excretory function is impaired. Some of these compounds are toxic at high concentrations and are usually known as “uremic toxins”. The cumulative detrimental effect of uremic toxins results in numerous health problems and eventually mortality during acute or chronic uremia, especially in end-stage renal disease. More than 100 different solutes increase during uremia; however, the exact origin for most of them is still debatable. There are three main sources for such compounds: exogenous ones are consumed with food, whereas endogenous ones are produced by the host metabolism or by symbiotic microbiota metabolism. In this article, we identify uremic retention solutes presumably of gut microbiota origin. We used database analysis to obtain data on the enzymatic reactions in bacteria and human organisms that potentially yield uremic retention solutes and hence to determine what toxins could be synthesized in bacteria residing in the human gut. We selected biochemical pathways resulting in uremic retention solutes synthesis related to specific bacterial strains and revealed links between toxin concentration in uremia and the proportion of different bacteria species which can synthesize the toxin. The detected bacterial species essential for the synthesis of uremic retention solutes were then verified using the Human Microbiome Project database. Moreover, we defined the relative abundance of human toxin-generating enzymes as well as the possibility of the synthesis of a particular toxin by the human metabolism. Our study presents a novel bioinformatics approach for the elucidation of the origin of both uremic retention solutes and uremic toxins and for searching for the most likely human microbiome producers of toxins that can be targeted and used for the therapy of adverse consequences of uremia.

The Prescription of Drugs That Inhibit Organic Anion Transporters 1 or 3 Is Associated with the Plasma Accumulation of Uremic Toxins in Kidney Transplant Recipients

The renal elimination of uremic toxins (UTs) can be potentially altered by drugs that inhibit organic anion transporters 1/3 (OAT1/OAT3). The objective of the present study was to determine whether the prescription of at least one OAT1/OAT3 inhibitor was associated with the plasma accumulation of certain UTs in kidney transplant recipients. We included 403 kidney transplant recipients. For each patient, we recorded all prescription drugs known to inhibit OAT1/OAT3. Plasma levels of four UTs (trimethylamine N-oxide (TMAO), indole acetic acid (IAA), para-cresylsulfate (pCS), and indoxylsulfate (IxS) were assayed using liquid chromatography-tandem mass spectrometry. Plasma UT levels were significantly higher among patients prescribed at least one OAT inhibitor (n = 311) than among patients not prescribed any OAT inhibitors (n = 92). Multivariate analysis revealed that after adjustment for age, estimated glomerular filtration rate (eGFR), plasma level of albumin and time since transplantation, prescription of an OAT1/OAT3 inhibitor was independently associated with the plasma accumulation of pCS (adjusted odds ratio (95% confidence interval): 2.11 (1.26; 3.61]). Our results emphasize the importance of understanding the interactions between drugs and UTs and those involving UT transporters in particular.

Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence

Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic toxins in CKD has become the conventional treatment in the clinic. However, studies rarely pay attention to uremic toxin clearance in the early stage of acute kidney injury (AKI) to prevent progression to CKD despite increasing reports demonstrating that uremic toxins are correlated with the severity of injury or mortality. This review highlights the current evidence of uremic toxin accumulation in AKI and the therapeutic value to prevent CKD progression specific to protein-bound uremic toxins (PBUTs).

Rhubarb Enema Decreases Circulating Trimethylamine N-Oxide Level and Improves Renal Fibrosis Accompanied With Gut Microbiota Change in Chronic Kidney Disease Rats

Objectives: Trimethylamine N-oxide (TMAO), a metabolic product of gut flora, is increased in chronic kidney disease (CKD) subjects and is recognized as one type of uremic toxins which is associated with poor cardiovascular outcomes and kidney function loss. Previous studies have suggested that rhubarb enema could reduce circulating uremic toxins such as urea, creatinine, and indoxyl sulfate and also regulate the intestinal microbiota. However, whether rhubarb enema retards kidney dysfunction by reducing circulating TMAO and its underlying mechanism, are still unclear. The present study aims to investigate the impact of rhubarb enema on TMAO and its precursors, as well as on the intestinal microbiota in 5/6 nephrectomized (5/6Nx) CKD rats.Design: Rats in the treatment groups were given rhubarb enema after modeling. At the end of the study, blood, feces, and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses.Results: Rhubarb enema reduced serum TMAO and trimethylamine (TMA) levels, inhibited the expression of inflammatory markers (interleukin-6, tumor necrosis factor α and Interferon-γ) and alleviated tubular atrophy, monocyte infiltration and interstitial fibrosis in 5/6Nx CKD rats. Moreover, rhubarb enema significantly increased the abundance of some symbiotic bacteria and probiotics, while reduced the abundance of some potential pathogens at the genus level. In addition, Spearman’s correlation analysis revealed that lachnospiraceae and romboutsia were positively correlated with TMAO.Conclusion: Rhubarb enema decreases circulating TMAO level and improves renal fibrosis in 5/6Nx CKD rats, which may be related to the regulation of intestinal microbial community.

Effect of nutritionally complete formula on gut microbiota and their metabolite in fecal batch fermentation system

Background: Emerging evidence has revealed that the gut microbiota is significantly altered, contributing to the occurrence and development of chronic kidney disease (CKD). Therefore, the target of increasing short-chain fatty acids (SCFAs) and lactic acid production and reduction of uremic toxins were interested. Objective: To study the effect of the nutritionally complete formula (Synplus) developed for hemodialysis patients on gut microbiota and their metabolite in in vitro fecal fermentation of healthy volunteers.Methods: Fecal fermentation (in vitro) using batch culture in an environment mimicking human large intestine was used to study the change of gut microbiota by next generation sequencing (NGS) during fermentation of the developed formula (Synplus), commercial formula (Nepro®) and control. The gut metabolites were determined including short-chain fatty acids (acetic, propionic, and butyric) and lactic acid. The uremic toxins (p-cresol and indole) were determined by high performance liquid chromatography (HPLC).Results: The increase of Lactobacillus spp. (53.74%) and Bifidobacterium spp. (29.35%) was observed in the developed product (Synplus) compared with control at 48 hrs fermentation meanwhile, these genera were decreased in a commercial product (Nepro®). Moreover, the abundance of the genus Escherichia spp. (12.33%) was observed in Nepro® fermentation, with Escherichia albertii species which is a newly discovered pathogen of the gastrointestinal tract. Microbial metabolites produced by fecal fermentation of Synplus revealed that propionate, acetate, and butyrate increased significantly (p<0.05). All the samples evaluated exhibited acetate in abundance when compared to other SCFAs. Acetate was the most abundant SCFA in all samples. The concentrations of acetate for Synplus fermentation were 15.63±3.26, 147.29±2.39, 162.28±4.13 and 189.39±0.17 mM at 0, 12, 24, and 48 hrs respectively. Total SCFAs produced from Synplus was significantly increased (p<0.05) and higher than control and Nepro®, respectively. The concentration of p-cresol at 48 hrs fermentation for control, Synplus and Nepro® were 3.79±0.12, 6.31±2.37 and 11.59±0.10 µg/mL, respectively. The indole concentration of control, Synplus and Nepro® were 3.64±0.08, 15.06±3.56 and 12.81±1.68 µg/mL, respectively. There were also indicated that imbalance of gut microbiota was related with the ratio of uremic toxins (indole and p-cresol) to SCFAs.CONCLUSION: The synbiotic product containing prebiotic and probiotic may be used to improve gut microbiota thus reducing the risk of kidney disease.Keywords: synbiotic, gut microbiota, uremic toxins, SCFA, CKD

Effect of Nutrition on Age-Related Metabolic Markers and the Gut Microbiota in Cats

Age-related changes in the gut microbiota and metabolites are associated with the increased risk of detrimental conditions also seen with age. This study evaluated whether a test food with potential anti-aging benefits results in favorable changes in plasma and fecal metabolites and the fecal microbiota in senior cats. Forty healthy domestic cats aged 8.3–13.5 years were fed a washout food for 30 days, then control or test food for 30 days. After another 30-day washout, cats were switched to the other study food for 30 days. Assessment of plasma and fecal metabolites showed lower levels of metabolites associated with detrimental processes (e.g., uremic toxins) and higher levels of metabolites associated with beneficial processes (e.g., tocopherols) after cats consumed the test food compared with the control food. A shift toward proteolysis with the control food is supported by higher levels of amino acid metabolites and lower levels of carbohydrate metabolites. Operational taxonomic units of greater abundance with the test food positively correlated with carbohydrate and nicotinic acid metabolites, and negatively correlated with uremic toxins, amino acid metabolism, secondary bile salts, and branched-chain fatty acids. Taken together, the test food appears to result in greater levels of metabolites and microbiota associated with a healthier state.