Effect of dietary synbiotic supplementation on serum indoxyl sulfate in prevalent hemodialysis patients

Background Indoxyl sulfate (IS) is produced by action of the intestinal flora on tryptophan in protein diet, and it is normally excreted by the kidney. IS is a protein-bound uremic toxin, and it is difficult to be removed by conventional hemodialysis (HD) methods; so, it accumulates in HD patients and may contribute to major cardiovascular morbidity and mortality. Aim To study the effect of dietary synbiotic (prebiotic and probiotic) supplementation on IS level in prevalent HD patients. Patients and methods This single-blind, placebo-controlled trial was conducted on 80 prevalent HD patients (between January 2017 and March 2017) in Ain Shams University Hospital. Patients were divided into 2 groups: group 1 was given synbiotic (SYN) and group 2 was given placebo for 6 weeks. Blood levels of IS, CRP, creatinine, blood urea nitrogen (BUN), sodium, potassium, calcium, and phosphorus were measured at baseline and after 6 weeks. Results There was a significant reduction in serum IS level in groups 1 and 2 in comparison to their baselines (P value = 0.000 and 0.019 respectively); however, the change in IS level in group 1 after SYN supplementation (64% with IR 72.38–33.33) was more than that shown in group 2 (did not receive SYN) (18.47% with IR 26.75–26.75) with a highly significant P value, 0.000. Also, there were significant reductions in the levels of creatinine, BUN, phosphorus (P values < 0.001), and CRP (P values 0.002) in group 1 respectively with no similar changes noticed in group 2. Conclusion SYN supplementation in HD patients can reduce serum levels of IS and other uremic toxins like BUN and creatinine. Also, it may help to reduce serum phosphorus and CRP levels.

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.

Renoprotection of Selected Antioxidant-Rich Foods (Water Spinach and Red Grape) and Probiotics in Gentamicin-Induced Nephrotoxicity and Oxidative Stress in Rats

Objectives: The current study investigated the curative effects of two selected antioxidant-rich foods (water spinach and red grape) and probiotics on the kidney exposed to nephrotoxicity induced by gentamicin. Methods: A total of 30 Wistar Albino female rats equally divided into six groups were studied for seven days. Except for the normal control (NC) group, all groups received 80 mg/kg/day gentamicin (GEN) injection intra-peritoneally for seven days. NC and GEN groups received only regular diet. In the water spinach group (GEN + WS) and red grape (GEN + RG) groups, rats were provided with 20 g/rat/day of boiled water spinach and 5 mL/rat/day of red grape juice, respectively. The probiotic (GEN + P4) and (GEN + P8) groups received 4 × 109 and 8 × 109 viable bacteria, respectively. On the 8th day, all the rats were sacrificed to collect blood and kidney. Serum creatinine, urea, uric acid, malondialdehyde (MDA), nitric oxide (NO), and superoxide dismutase (SOD) were analyzed. In addition, kidney histopathology was taken for final observation. Results: Both antioxidant-rich foods and probiotic (P4) significantly (p < 0.05) attenuated the GEN-induced oxidative and nitrosative stress and improved kidney function by lowering uremic toxin (serum creatinine, and uric acid) levels. Histopathological findings of kidney tissues of all groups were consistent with the biochemical findings. Conclusion: The current preclinical study suggests that the consumption of antioxidant-rich foods might be a promising fighting option against gentamycin-induced nephrotoxicity and oxidative stress. However, extensive studies and clinical monitoring are immediately required to determine the appropriate probiotic doses and mechanism of action for such effects.

An online atlas of human plasma metabolite signatures of gut microbiome composition

The human gut microbiota produces a variety of small compounds, some of which enter the bloodstream and impact host health. Conversely, various exogenous nutritional and pharmaceutical compounds affect the gut microbiome composition before entering circulation. Characterization of the gut microbiota—host plasma metabolite interactions is an important step towards understanding the effects of the gut microbiota on human health. However, studies involving large and deeply phenotyped cohorts that would reveal such meaningful interactions are scarce. Here, we used deep metagenomic sequencing and ultra-high-performance liquid chromatography linked to mass spectrometry for detailed characterization of the fecal microbiota and plasma metabolome, respectively, of 8,584 participants invited at age 50 to 64 of the Swedish CArdioPulmonary bioImage Study (SCAPIS). After adjusting for multiple comparisons, we identified 1,008 associations between species alpha diversity and plasma metabolites, and 318,944 associations between specific gut metagenomic species and plasma metabolites. The gut microbiota explained up to 50% of the variance of individual plasma metabolites (mean of 4.7%). We present all results as the searchable association atlas "GUTSY" as a rich resource for mining associations, and exemplify the potential of the atlas by presenting novel associations between oral medication and the gut microbiome, and microbiota species strongly associated with levels of the uremic toxin p-cresol sulfate. The association atlas can be used as the basis for targeted studies of perturbation of specific bacteria and for identification of candidate plasma biomarkers of gut flora composition.

Association between Cardiac Outcomes and Indoxyl Sulfate Levels in Hemodialysis Patients: A Cross-sectional Study

Objective Indoxyl sulfate (IS) is a protein-bound uremic toxin that is associated with cardiovascular events and mortality in hemodialysis (HD) patients. However, the factors affecting the levels of IS are currently unclear. This study aimed to investigate the factors influencing serum IS concentrations in HD patients. Methods We included 100 HD patients from Guangdong Provincial People’s Hospital. Baseline characteristics, including sex, age, clinical features, duration of HD, echocardiography findings, electrocardiogram results, and biochemical indicators, were collected and analyzed in relation to serum total-form IS levels. Results Among all 100 patients, serum IS levels were significantly higher in patients aged ≥ 60 years, males, and patients with mitral regurgitation and inadequate dialysis. Among patients aged < 60 years, IS levels were significantly higher among patients with mitral regurgitation compared with those without. Furthermore, multiple linear regression analysis identified sex, age, ventricular septal thickness, and mitral regurgitation as factors independently associated with serum IS (STDβ = −0.475, 0.162, −0.153, 0.142, and 0.136, respectively; all P < 0.05) adjusted for body mass index, smoking, and fasting plasma glucose. Conclusions Male sex, age ≥ 60 years, ventricular septal thickness, and mitral regurgitation are factors associated with high total serum IS concentrations in Chinese HD patients. Elevated IS levels may play a role in the process of mitral regurgitation in HD patients < 60 years old.

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).

Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT/NADPH Oxidase/ROS Pathway

Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial–mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.

Sodium Dialysate Prescription in a New Dialysis Facility

As the Medical Director of this new dialysis facility, I recommend a fixed sodium dialysate (Nadial) concentration at 138 mEq/L. This relates to my former experience in the Tassin unit in France and the fear of sodium as a powerful uremic toxin. I realize that, according to the Na+ set-point theory, a fixed value of the Nadial may create a plasma–dialysate (P–D) gradient and may favor intradialytic plasma Na+ changes. In cases where this is associated with signs of negative Na+ balance (bad session tolerance/quality of life) or positive Na+ balance (high interdialytic weight gain or high blood pressure), individualization of the Nadial to reduce the P–D gradient and change in plasma Na+ concentration may be useful, even though evidence remains scarce. I look forward to the possibility of using new dialysis machines that allow for the evaluation of sodium balance and tailoring of the sodium diffusion process.

Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs

Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the accumulation of uremic toxins in the blood of DM/CKD patients are known mechanisms for the pathogenesis of CVD. However, the molecular factors that cause this disproportional increase in CVD in the DM/CKD population are still unknown. Since long non-protein-coding RNAs (lncRNAs) play an important role in regulating multiple cellular functions, we used human endothelial cells treated with high glucose to mimic DM and with the uremic toxin indoxyl sulfate (IS) to mimic the endothelial injury associated with CKD. Differentially expressed lncRNAs in these conditions were analyzed by RNA sequencing. We discovered that lnc-SLC15A1-1 expression was significantly increased upon IS treatment in comparison with high glucose alone, and then cascaded the signal of chemokines CXCL10 and CXCL8 via sponging miR-27b, miR-297, and miR-150b. This novel pathway might be responsible for the endothelial inflammation implicated in augmenting CVD in DM/CKD and could be a therapeutic target with future clinical applications.