Uremic Toxins Research Articles

(Poly)phenol-rich grape and blueberry extract prevents LPS-induced disruption of the blood-brain barrier through the modulation of the gut microbiota-derived uremic toxins

The dynamic protective capacity of (poly)phenols, attributed to their potent antioxidant and anti-inflammatory properties, has been consistently reported. Due to their capacity to alter gut microbiome composition, further actions of (poly)phenols may be exerted through the modulation of the microbiota-gut-brain axis. However, the underlying mechanisms remain poorly defined. Here, we investigated the protective effect of a (poly)phenol-rich grape and blueberry extract (Memophenol™), on the microbiota-gut-brain axis in a model of chronic low-grade inflammation (0.5 mg/kg/wk lipopolysaccharide (LPS) for 8 weeks). Dietary supplementation of male C57BL/6 J mice with Memophenol™ prevented LPS-induced increases in the microbe-derived uremia-associated molecules, indoxyl sulfate (IS) and trimethylamine N-oxide (TMAO). These changes coincided with shifts in gut microbiome composition, notably Romboutsia and Desulfovibrio abundance, respectively. In the brain, LPS exposure disrupted the marginal localisation of the endothelial tight junction ZO-1 and downregulated ZO-1 mRNA expression to an extent closely correlated with TMAO and IS levels; a process prevented by Memophenol™ intake. Hippocampal mRNA sequencing analysis revealed significant downregulation in regulatory pathways of neurodegeneration with Memophenol™ intake. These findings may indicate a novel protective role of the (poly)phenol-rich grape and blueberry extract on the endothelial tight junction component ZO-1, acting through modulation of gut microbial metabolism.

In laying hens, chronic heat stress-induced renal fibrosis is potentially promoted by indoxyl sulfate

Indoxyl sulfate (IS), a uremic toxin, is a harmful factor that damages kidneys. Chronic heat stress in laying hens causes renal injury; however, whether IS accumulation is involved in this injury remains unknown. We selected 20 Boris brown laying hens (27 weeks old) and randomly assigned them to two groups (n = 10), one group was exposed to chronic heat stress (32 °C for 4 weeks), whereas the other was maintained at 24 °C. Chronic heat exposure significantly increased plasma and renal IS concentrations (P < 0.05). Exposure to heat also increased renal expression of the aryl hydrocarbon receptor (AhR) and its target genes (CYP1A4 and CYP1B1). Furthermore, chronic heat exposure tended to increase the 2-thiobarbituric acid reactive substances content (P = 0.08) and significantly decreased the antioxidant capacity in the kidney, while increasing the transcription levels of nuclear factor κB and fibrosis-related genes (COLA1A1, αSMA, TGF-β, Smad3, and VCAM-1) and the area of renal fibrosis. Our results indicate that chronic heat exposure induces systemic and renal IS accumulation in laying hens. This accumulated IS may activate the AhR pathway and chronically disrupt the oxidative stress status and antioxidant activity, thus promoting renal fibrosis and dysfunction in laying hens.

Dietary protein intake and the tubular handling of indoxyl sulfate.

Chronic kidney disease (CKD) patients are advised to limit their protein intake. A high protein diet is known to induce glomerular hyperfiltration, as well as hypertrophy of the remnant kidney, and glomerulosclerosis. Whether the diet causes changes in kidney tubule transport via gut microbiome metabolites is still unknown. We hypothesized that protein intake affects not only the intestinal generation and absorption, but also the kidney disposal of microbial amino acid metabolites. We combined data from animal models and human studies. 5/6th nephrectomy rats were administered a high (HP) or low-protein (LP) diet for 7 weeks. Plasma and urine concentration of the uremic toxins (UTs) indoxyl sulfate (IS), p-cresyl sulfate (PCS), and p-cresyl glucuronide (PCG) were measured. Their fractional excretion (FE) was calculated. The expression of kidney membrane transporters OAT1, OAT3, BCRP, OCT2 and MRP4 was analyzed. Differences in FE of UTs between individuals with higher and lower protein intake in two CKD cohorts were sought. CKD rats on an HP diet showed increased plasma levels of PCS and PCG but not IS compared to rats on a LP diet. Conversely, urinary excretion and FE of IS were higher in the HP CKD group. BCRP, MRP4 and OCT2 were not influenced by the diet. OAT1 and OAT3 were upregulated in the HP CKD group. In two independent cohorts of CKD patients, individuals with a high dietary protein intake showed a significantly higher FE of IS. A HP diet leads to a higher generation and/or absorption of aminoacid-derived UT precursors in CKD rodent models and humans, most likely via gut microbiome modulation. We demonstrate that dietary protein intake modulates transcription and expression of OAT1 and OAT3, corroborating the existence of the remote sensing and signaling hypothesis. Dietary protein intake influences kidney physiology beyond glomerular filtration.

Effects of High Amylose-Resistant Starch on Gut Microbiota and Uremic Toxin Levels in Patients With Stage-G3a-G4 Chronic Kidney Disease: A Randomized Trial

ObjectiveThis study was designed to determine the effect of 16 weeks of supplementation with Hi-maize 260 resistant starch on the gut microbiota, uremic toxins (indoxyl sulfate and p-cresyl sulfate), markers of inflammation and oxidative stress along with vascular function in patients with stage G3a-G4 chronic kidney disease (CKD). Design& Methods: This was a double-blind, placebo-controlled, parallel-arm, randomized controlled trial. Sixty-eight patients with stage G3a-G4 CKD were randomized to either resistant starch with usual care or placebo and usual care. Patients attended four testing sessions: two baseline visits, and follow-up visits at 8 and 16 weeks. Fasting blood samples, resting brachial and central blood pressures, along with arterial stiffness, were collected at visits (1 or 2), and weeks 8 and 16. A stool sample was collected for analysis of microbial composition at baseline and week 16. Patients were randomized after the baseline visits. ResultsPatients receiving the resistant starch had a reduction in p-cresyl sulfate at week 16. This reduction was associated with a decrease in microbial α-diversity between baseline and week 16 (Chao1 p=0.014, Shannon p=0.017, PD p= 0.046, and Simpson p=0.017) as well as increases in Subdoligranulum (p=0.03) and Oscillospiraceae UCG 002 (p=0.02) and decreases in Bacteroides (p=0.009).There were no changes in microbial beta diversity and other biomarkers or markers of vascular function following the 16-week period Conclusion: Sixteen weeks of supplementation of resistant starch in patients with stage G3a-G4 CKD led to changes in microbial composition that were associated with a significant reduction in p-cresyl sulfate.

Copper Accumulations as a Uremic Toxin in CKD

Copper Accumulations as a Uremic Toxin in CKD

Bimetallic metal organic frameworks-based nanozyme for colorimetry/fluorescence dual-mode uremic toxin detection

Chronic kidney disease (CKD) can greatly increase the mortality risk for clinical patients, with a major challenge being the accurate detection of uremic toxins. Metal organic frameworks (MOFs)-based colorimetry/fluorescence dual-mode probe have shown great potential for bio-detection. However, one of the challenges for MOFs-based nanoprobe is to effectively improve the activity of mimetic enzymes for colorimetric assays while maintaining their outstanding luminescence response for fluorescence sensing. Here, we developed a novel bimetallic Zr/Ce-MOFs, which possesses high catalytic activity and excellent luminescence properties for dual-mode sensing of uremic toxins. The co-existence of Ce and Zr in the MOFs improves the catalytic activity for colorimetric detection of phosphate ions (one type of uremic toxins) and the strong coordinate covalent interaction between phosphate ions and Zr/Ce leads to a significant fluorescence enhancement of the MOFs. Furthermore, we achieved high sensitivity phosphate ions analysis in serum samples. This strategy provides an easy and reliable platform for the detection of uremic toxins in complicated physiological environment.

Mesoporous activated carbon derived from Chinese herbal medicine residues for hemoperfusion removal of uremia toxins from progressive chronic kidney diseases patients

Hemoperfusion is one of the most important therapies for progressive chronic kidney disease (CKD) and is effective at removing toxins from the blood. Increasing the efficiency of adsorbents applied in hemoperfusion is crucial. In the present study, shell of areca nut, one of the most common waste Chinese herb medicine residue with a porous structure was carbonized and activated at different temperatures to obtain two kinds of porous materials. The biocompatibility of the as-prepared porous materials was estimated via a hemolytic test, and the removal efficiency of the materials toward toxins was tested via an adsorption experiment in solution and blood samples from CKD patients, simulated hemoperfusion and in vivo hemoperfusion. After 4 h of adsorption, free and protein-bound toxins in solution were efficiently removed by the prepared porous materials, and the removal efficiency was better than that of commonly used hemoperfutor adsorbents. Most of the tested toxins can be removed from CKD blood samples and simulated hemoperfusion samples. Blood uremic toxins from CKD mice were also efficiently and safely removed after in vivo hemoperfusion using the as-prepared adsorbent. This work highlights promising adsorbents for hemoperfusion that could increase the therapeutic efficacy in patients with progressive CKD.

Comparative Effects of Acetate- and Citrate-Based Dialysates on Dialysis Dose and Protein-Bound Uremic Toxins in Hemodiafiltration Patients: Exploring the Impact of Calcium and Magnesium Concentrations.

Modern hemodialysis employs weak acids as buffers to prevent bicarbonate precipitation with calcium or magnesium. Acetate, the most used acid, is linked to chronic inflammation and poor dialysis tolerance. Citrate has emerged as a potential alternative, though its effect on dialysis efficiency is not clear. This study aims to compare the efficacy of acetate- and citrate-based dialysates, focusing on protein-bound uremic toxins and dialysis doses. This single-center prospective crossover study includes prevalent patients participating in a thrice-weekly online hemodiafiltration program. Four dialysates were tested: two acetate-based (1.25 and 1.5 mmol/L calcium) and two citrate-based (1.5 mmol/L calcium with 0.5 and 0.75 mmol/L magnesium). Pre- and post-dialysis blood samples of eighteen patients were analyzed for urea, creatinine, p-cresyl sulfate, indoxyl sulfate, and albumin. Statistical significance was assessed using paired t-tests and repeated measures of ANOVA. There were no significant differences in dialysis dose (Kt), urea, creatinine, or indoxyl sulfate reduction ratios between acetate- and citrate-based dialysates. However, a significant decrease in the reduction ratio of p-cresyl sulfate was observed with the acetate dialysate containing 1.25 mmol/L calcium and the citrate dialysate with 0.5 mmol/L magnesium compared to the acetate dialysate containing 1.5 mmol/L calcium and the citrate dialysate with 0.75 mmol/L magnesium (51.56 ± 4.75 and 53.02 ± 4.52 vs. 65.25 ± 3.38 and 58.66 ± 4.16, p 0.007). No differences in dialysis dose were found between acetate- and citrate-based dialysates. However, citrate dialysates with lower calcium and magnesium concentrations may reduce the albumin displacement of p-cresyl sulfate. Further studies are needed to understand the observed differences and optimize the dialysate composition for the better clearance of protein-bound uremic toxins.

Quantification of Uremic Toxins in Pediatric CKD: A Potential Biomarker and Mechanistic Driver of Cardiorenal Syndrome

Quantification of Uremic Toxins in Pediatric CKD: A Potential Biomarker and Mechanistic Driver of Cardiorenal Syndrome

Hemodialysis Coupled with Hemadsorption: Benefits on Uremic Toxins Retention and Oxidative Stress

Hemodialysis Coupled with Hemadsorption: Benefits on Uremic Toxins Retention and Oxidative Stress

Total alkaloids of Aconitum carmichaelii Debx alleviate cisplatin-induced acute renal injury by inhibiting inflammation and oxidative stress related to gut microbiota metabolism

BackgroundCisplatin-induced acute kidney injury (AKI) is a complex and serious clinical issue, representing a major cause of hospital-acquired AKI. Alkaloids are the main active constituents of Aconitum carmichaelii Debx, which exhibit protective effects in several kidney disease models and against other acute organ injuries. However, its activity and mechanism of action in AKI treatment remain unclear. PurposeThis study aimed to elucidate the effect of Aconitum carmichaelii Debx (ACA) in a model of cisplain-induced AKI and comprehensively investigate its underlying mechanisms. MethodsThe major alkaloids in ACA were analyzed using high-performance liquid chromatography. Blood urea nitrogen (BUN) and serum creatine levels were measured using automated biochemical instruments. 16S rRNA sequencing, short-chain fatty acid (SCFA) analysis, fecal microbiota transplantation (FMT), non-targeted metabolomics, and transcriptomics were performed to systematically identify prospective biomarkers after ACA treatment. Anti-inflammatory and anti-oxidative stress activities were monitored using ELISA and western blotting. ResultsFour main compounds (fuziline, neoline, talatisamine, and songorine) were identified in ACA. ACA significantly alleviated cisplatin-induced AKI by reducing (BUN) and serum creatine levels and improving histopathological scores. Moreover, ACA balanced cisplatin-mediated confoundments in microbial composition and function, including decreasing the levels of Escherichia-Shigella, Clostridium, and Ruminococcus, as well as increasing Ligilactobacillus, Anaerotruncus, Bacteroides and Desulfovibrio levels, accompanied by uremic toxin reduction, and augmenting serum SCFAs. The FMT experiments further confirmed that ACA exerts anti-AKI effects by affecting gut microbiota. A multi-omics study has shown that ACA regulates glutathione and tryptophan metabolism and mediates pathways that trigger inflammatory responses. Finally, ACA reduced serum levels of inflammatory factors (IL-1β, IL-6, and TNF-α), restored enzymes of the antioxidative system (SOD and CAT) and GSH values, and decreased monoester diterpene alkaloid levels in the kidney by inhibiting the expression of NF-κB pathway-related proteins and increasing Nrf2/HO-1 pathway-related protein expression. ConclusionACA protects against cisplatin-induced AKI through its anti-inflammatory and antioxidant functions, which may be associated with the restoration of gut microbiota metabolism. ACA is a potential drug for AKI and other forms of organ damage related to the disruption of the gut microbiota.

Identification of Gut Microbiota Involved in the Production of Uremic Toxins in Patients with CKD

Identification of Gut Microbiota Involved in the Production of Uremic Toxins in Patients with CKD

Comparison of Protein-Bound and Large Molecular-Weight Uremic Toxin Removals with Novel Super High-Flux Dialyzer between Hemodialysis (HD) and High-Volume Online Hemodiafiltration Modalities: A Cross-Over Randomized Controlled Study

Comparison of Protein-Bound and Large Molecular-Weight Uremic Toxin Removals with Novel Super High-Flux Dialyzer between Hemodialysis (HD) and High-Volume Online Hemodiafiltration Modalities: A Cross-Over Randomized Controlled Study

Activation of Aryl Hydrocarbon Receptor by an Indolic Uremic Toxin Increases the Risk of Deep Venous Thrombosis

Activation of Aryl Hydrocarbon Receptor by an Indolic Uremic Toxin Increases the Risk of Deep Venous Thrombosis

Uremic Toxin Indoxyl Sulfate Increases Osteocyte Wnt Inhibitor Signaling and Decreases RANKL and Mineralization, Effects Negated by PTH

Uremic Toxin Indoxyl Sulfate Increases Osteocyte Wnt Inhibitor Signaling and Decreases RANKL and Mineralization, Effects Negated by PTH

P-cresyl Sulfate and Indoxyl Sulfate: Uremic Toxins Implicated in the Progression of Colorectal Cancer in Individuals with CKD

P-cresyl Sulfate and Indoxyl Sulfate: Uremic Toxins Implicated in the Progression of Colorectal Cancer in Individuals with CKD

Impact of the mediterranean diet on dietary fiber intake and serum uremic toxins in patients treated with peritoneal dialysis

Impact of the mediterranean diet on dietary fiber intake and serum uremic toxins in patients treated with peritoneal dialysis

Impact of Fermentable and Viscous Dietary Fiber on Gut-Derived Uremic Toxins in Rats with Progressive CKD

Impact of Fermentable and Viscous Dietary Fiber on Gut-Derived Uremic Toxins in Rats with Progressive CKD

Angiotensin-Converting Enzyme 2 in AKI Was Attenuated by Uremia Toxin Indoxyl Sulfate and Restored by Renin-Angiotensin-Aldosterone System Inhibitors

Angiotensin-Converting Enzyme 2 in AKI Was Attenuated by Uremia Toxin Indoxyl Sulfate and Restored by Renin-Angiotensin-Aldosterone System Inhibitors

Does the Composition of Gut Microbiota Affect Chronic Kidney Disease? Molecular Mechanisms Contributed to Decreasing Glomerular Filtration Rate.

Chronic kidney disease (CKD) is a very prevalent and insidious disease, particularly with initially poorly manifested symptoms that progressively culminate in the manifestation of an advanced stage of the condition. The gradual impairment of kidney function, particularly decreased filtration capacity, results in the retention of uremic toxins and affects numerous molecular mechanisms within the body. The dysbiotic intestinal microbiome plays a crucial role in the accumulation of protein-bound uremic toxins such as p-cresol (pC), indoxyl sulfate (IS), and p-cresyl sulfate (p-CS) through the ongoing fermentation process. The described phenomenon leads to an elevated level of oxidative stress and inflammation, subsequently resulting in tissue damage and complications, particularly an increase in cardiovascular risk, representing the predominant cause of mortality in chronic kidney disease (CKD). Therefore, exploring methods to reduce uremic toxins is currently a pivotal therapeutic strategy aimed at reducing the risk of organ damage in patients with chronic kidney disease (CKD). This review aims to summarize recent discoveries on modifying the composition of the intestinal microbiota through the introduction of special probiotic and synbiotic supplements for CKD therapy. The potential to connect the gut microbiota with CKD opens the possibility for further extensive research in this area, which could lead to the incorporation of synbiotics and probiotics into the fundamental treatment and prevention of CKD.