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Kidney dysfunction leads to the retention of metabolites within the blood that are not effectively cleared with conventional hemodialysis. Magnetic nanoparticle (MNP)-based absorbents have inherent properties that make them amenable to capturing toxins in the blood, notably a large surface area that can be chemically modified to enhance toxin capture and the ability to be easily collected from the blood using an external magnetic field. Cyclodextrins (CDs) present a chemical structure that facilitates the binding of small molecules. However, the hemocompatibility of MNPs modified with films composed of different native types of CDs (α, β, or γ) has not yet been investigated, which is information crucial to the potential clinical application of MNPs to supplement hemodialysis. To this end, films of α-, β-, or γ-CDs were formed on MNPs and characterized. The impact of these films on the adsorbed protein structure, composition of key adsorbed proteins, and clotting kinetics were evaluated. It was found that modified MNPs did not significantly affect the secondary structure of some proteins (albumin, lysozyme, α-lactalbumin). The adsorbed proteome from platelet-poor human plasma was evaluated as a function of film properties. Compared to non-modified nanoparticles, CD-modified MNPs exhibited a significant decrease in the adsorbed protein per surface area of MNPs. The immunoblot results showed variations in the adsorption levels of C3, fibrinogen, antithrombin, Factor XI, and plasminogen across CD-modified MNPs. The hemocompatibility experiments showed that CD-modified MNPs are compatible with human whole blood, with no significant impact on platelet activation, hemolysis, or hemostasis. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) can lead to cardiac dysfunction in a condition known as cardiorenal syndrome (CRS). It is postulated that the accumulation of uremic toxins in the bloodstream, as a consequence of declining kidney function, may contribute to these adverse cardiac effects. While CRS in adults has been extensively studied, there is a significant knowledge gap with pediatric patients. Uremic toxin levels in children remain inadequately characterized and quantified compared to adults. This review aims to systematically evaluate the association between uremic toxin concentrations and cardiac changes in pediatric CRS and to examine the impact of different dialysis modalities, specifically hemodialysis and peritoneal dialysis, on uremic toxin clearance and cardiovascular parameters. To address this, we conducted a systematic literature search of PubMed, following PRISMA guidelines. We used the terms "uremic toxins" and "cardiorenal syndrome" with variations in syntax to search for studies discussing the relationship between uremic toxin levels in CKD, the subsequent impact on cardiac parameters, and the emergence of cardiac dysfunction. Full-text articles written in English, conducted on humans aged from birth to 18 years, and published until December 2021 were included. A comprehensive literature search yielded six studies, and their risk of bias was assessed using JBI Critical Appraisal Checklists. Our systematic review is registered on PROSPERO, number CRD42023460072. This synthesis intends to provide an understanding of the role of uremic toxins in pediatric CRS. The findings reveal that pediatric patients with end-stage CKD on dialysis exhibit elevated uremic toxin levels, which are significantly associated with cardiovascular disease parameters. Additionally, the severity of CKD correlated with higher uremic toxin levels. No conclusive evidence was found to support the superiority of either hemodialysis or peritoneal dialysis in terms of uremic toxin clearance or cardiovascular outcomes. More pediatric-specific standardized and longitudinal studies are needed to develop targeted treatments and improve clinical outcomes and the quality of life for affected children. [ABSTRACT FROM AUTHOR]

In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation.

• Metabolome analysis revealed that plasma concentration of 3-indoxyl sulfate was increased in Slc17a3−/− mice compared to that in wild-type mice. • Urinary excretion of 3-indoxyl sulfate was reduced in Slc17a3−/− mice compared to that in wild-type mice. • An uptake study using NPT4-expressing oocytes revealed that 3-indoxyl sulfate is a physiological substrate of NPT4. • Our findings suggest that NPT4 regulates systemic exposure to 3-indoxyl sulfate by regulating its urinary excretion. Sodium-phosphate transporter NPT4 (SLC17A3) is a membrane transporter for organic anionic compounds localized on the apical membranes of kidney proximal tubular epithelial cells and plays a role in the urinary excretion of organic anionic compounds. However, its physiological role has not been sufficiently elucidated because its substrate specificity is yet to be determined. The present study aimed to comprehensively explore the physiological substrates of NPT4 in newly developed Slc17a3−/− mice using a metabolomic approach. Metabolomic analysis showed that the plasma concentrations of 11 biological substances, including 3-indoxyl sulfate, were more than two-fold higher in Slc17a3−/− mice than in wild-type mice. Moreover, urinary excretion of 3-indoxyl sulfate was reduced in Slc17a3−/− mice compared to that in wild-type mice. The uptake of 3-indoxyl sulfate by NPT4-expressing Xenopus oocytes was significantly higher than that by water-injected oocytes. The calculated K m and V max values for NPT4-mediated 3-indoxyl sulfate uptake were 4.52 ± 1.18 mM and 1.45 ± 0.14 nmol/oocyte/90 min, respectively. In conclusion, the present study revealed that 3-indoxyl sulfate is a novel substrate of NPT4 based on the metabolomic analysis of Slc17a3−/− mice, suggesting that NPT4 regulates systemic exposure to 3-indoxyl sulfate by regulating its urinary excretion. [ABSTRACT FROM AUTHOR]

Objective To explore the mediating role of depression between uremic toxins and cognitive function in end-stage renal disease(ESRD)patients, so as to provide a basis for early clinical intervention. Methods A retrospective study involved 49 predialysis ESRD patients diagnosed in the Nephrology Department of The First Affiliated Hospital of Xi'an Jiaotong University between August 2018 and October 2021, along with 50 healthy controls(HC). General information of the two groups was collected. Montreal Cognitive Assessment(MoCA), Auditory Verbal Learning Test-Huashan Version(AVLT-H), Trail Making Test A(TMT-A), Beck Depression Inventory(BDI), and Beck Anxiety Inventory(BAI)were used to collect data on cognitive function, anxiety, and depression in both groups. Serological indicators in the ESRD group were used to clarify the impact of uremic toxins on cognitive function. PROCESS v3.4.1 was applied to explore the relationship between uremic toxins, depression, and cognitive function, as well as the mediating effect of depression. Results Significant differences were found between the ESRD group and the HC group in MoCA total score(P<0.001), AVLT-H(word learning; short-term delay; long-term delay,P<0.001; word recognition, P=0.001), TMT-A(P<0.001), BDI(P<0.001), and BAI(P=0.009). Cystatin C was a negative influencing factor for short-term delay in AVLT-H(B=-0.834, P=0.019), while BDI was a negative influencing factor for long-term delay in AVLT-H(B=-0.102, P=0.002), word recognition in AVLT-H(B=-0.071, P<0.001), and MoCA total score(B=-0.135, P=0.002). BDI partially mediated the effect of cystatin C on short-term delay in AVLT-H(total effect, c=-0.3346; direct effect, c'=-0.223 5; mediating effect, a×b=-0.111 0; and mediating effect proportion, 33.2%)and long-term delay in AVLT-H(total effect, c=-0.318 7; direct effect, c'=-0.218 8; mediating effect, a×b=-0.099 9; and mediating effect proportion, 31.3%). Conclusion ESRD patients experience cognitive decline as well as anxiety and depression. Cystatin C and depression are both negative influencing factors for cognitive decline in ESRD patients. Cystatin C indirectly affects cognitive function in ESRD patients through depression. [ABSTRACT FROM AUTHOR]

The uremic toxin indoxyl sulfate (IS) has been related to the development of various medical conditions notably chronic kidney disease (CKD). Hence, quantification of this biomarker in biological fluids may be a diagnostic tool to evaluate renal system functionality. Numerous analytical methods including liquid chromatography, gas chromatography, spectroscopy, and electrochemical techniques have since been used to analyze IS in different biological fluids. The current review highlights the relevant studies that assessed IS with a special focus on sample preparation, which is essential to reduce or eliminate the effect of endogenous components from the matrix in bioanalysis.

Kidney dysfunction leads to the retention of metabolites within the blood that are not effectively cleared with conventional hemodialysis. Magnetic nanoparticle (MNP)-based absorbents have inherent properties that make them amenable to capturing toxins in the blood, notably a large surface area that can be chemically modified to enhance toxin capture and the ability to be easily collected from the blood using an external magnetic field. Cyclodextrins (CDs) present a chemical structure that facilitates the binding of small molecules. However, the hemocompatibility of MNPs modified with films composed of different native types of CDs (α, β, or γ) has not yet been investigated, which is information crucial to the potential clinical application of MNPs to supplement hemodialysis. To this end, films of α-, β-, or γ-CDs were formed on MNPs and characterized. The impact of these films on the adsorbed protein structure, composition of key adsorbed proteins, and clotting kinetics were evaluated. It was found that modified MNPs did not significantly affect the secondary structure of some proteins (albumin, lysozyme, α-lactalbumin). The adsorbed proteome from platelet-poor human plasma was evaluated as a function of film properties. Compared to non-modified nanoparticles, CD-modified MNPs exhibited a significant decrease in the adsorbed protein per surface area of MNPs. The immunoblot results showed variations in the adsorption levels of C3, fibrinogen, antithrombin, Factor XI, and plasminogen across CD-modified MNPs. The hemocompatibility experiments showed that CD-modified MNPs are compatible with human whole blood, with no significant impact on platelet activation, hemolysis, or hemostasis.

Chronic kidney disease (CKD) can lead to cardiac dysfunction in a condition known as cardiorenal syndrome (CRS). It is postulated that the accumulation of uremic toxins in the bloodstream, as a consequence of declining kidney function, may contribute to these adverse cardiac effects. While CRS in adults has been extensively studied, there is a significant knowledge gap with pediatric patients. Uremic toxin levels in children remain inadequately characterized and quantified compared to adults. This review aims to systematically evaluate the association between uremic toxin concentrations and cardiac changes in pediatric CRS and to examine the impact of different dialysis modalities, specifically hemodialysis and peritoneal dialysis, on uremic toxin clearance and cardiovascular parameters. To address this, we conducted a systematic literature search of PubMed, following PRISMA guidelines. We used the terms “uremic toxins” and “cardiorenal syndrome” with variations in syntax to search for studies discussing the relationship between uremic toxin levels in CKD, the subsequent impact on cardiac parameters, and the emergence of cardiac dysfunction. Full-text articles written in English, conducted on humans aged from birth to 18 years, and published until December 2021 were included. A comprehensive literature search yielded six studies, and their risk of bias was assessed using JBI Critical Appraisal Checklists. Our systematic review is registered on PROSPERO, number CRD42023460072. This synthesis intends to provide an understanding of the role of uremic toxins in pediatric CRS. The findings reveal that pediatric patients with end-stage CKD on dialysis exhibit elevated uremic toxin levels, which are significantly associated with cardiovascular disease parameters. Additionally, the severity of CKD correlated with higher uremic toxin levels. No conclusive evidence was found to support the superiority of either hemodialysis or peritoneal dialysis in terms of uremic toxin clearance or cardiovascular outcomes. More pediatric-specific standardized and longitudinal studies are needed to develop targeted treatments and improve clinical outcomes and the quality of life for affected children.

Background Chronic kidney disease (CKD) is associated with a significant decrease in muscle strength and mass, possibly related to muscle cell damage by uremic toxins. Here, we studied in vitro and in vivo the effect of indoxyl sulfate (IS), an indolic uremic toxin, on myoblast proliferation, differentiation and expression of myogenic regulatory factors (MRF)—myoblast determination protein 1 (MyoD1), myogenin (Myog), Myogenic Factor 5 (Myf5) and myogenic regulatory factor 4 (Myf6 /MRF4)—and expression of myosin heavy chain, Myh2. Methods C2C12 myoblasts were cultured in vitro and differentiated in myotubes for 7 days in the presence of IS at a uremic concentration of 200 µM. Myocytes morphology and differentiation was analyzed after hematoxylin-eosin staining. MRF genes' expression was studied using reverse transcription polymerase chain reaction in myocytes and 5/6th nephrectomized mice muscle. Myf6 /MRF4 protein expression was studied using enzyme-linked immunosorbent assay; MYH2 protein expression was studied using western blotting. The role of Aryl Hydrocarbon Receptor (AHR)—the cell receptor of IS—was studied by adding an AHR inhibitor into the cell culture milieu. Results In the presence of IS, the myotubes obtained were narrower and had fewer nuclei than control myotubes. The presence of IS during differentiation did not modify the gene expression of the MRFs Myf5, MyoD1 and Myog, but induced a decrease in expression of Myf6 /MRF4 and MYH2 at the mRNA and the protein level. AHR inhibition by CH223191 did not reverse the decrease in Myf6/ MRF4 mRNA expression induced by IS, which rules out the implication of the ARH genomic pathway. In 5/6th nephrectomized mice, the Myf6 /MRF4 gene was down-regulated in striated muscles. Conclusion In conclusion, IS inhibits Myf6/ MRF4 and MYH2 expression during differentiation of muscle cells, which could lead to a defect in myotube structure. Through these new mechanisms, IS could participate in muscle atrophy observed in CKD. [ABSTRACT FROM AUTHOR]

The profile of gut microbiota can vary according to host genetic and dietary characteristics, and be influenced by disease state and environmental stressors. The uremic dysbiosis results in a loss of biodiversity and overgrowth of microorganisms that may cause elevation of metabolic solutes such as trimethylamine N-oxide (TMAO), inducing pathogenic effects on its host. In patients with chronic kidney disease (CKD), TMAO levels are elevated because of a decreased clearance and an increased production from the uremic gut dysbiosis with a disrupted intestinal barrier and elevated enzymatic hepatic activity. Dietary precursors of TMAO are abundant in animal-derived foods such as red meat, egg yolk and other full-fat dietary products. TMAO is also found naturally in fish and certain types of seafood, with the TMAO content highly variable according to the depth of the sea where the fish is caught, as well as processing and storage. Although evidence points towards TMAO as being an important link to vascular damage and adverse cardiovascular outcomes, the evidence in CKD patients has not been consistent. In this review we discuss the potential dietary sources of TMAO and its actions on the intestinal microbiome as an explanation for the divergent results. We further highlight the potential of a healthy diet as one feasible therapeutic opportunity to prevent gut dysbiosis and reduce uremic toxin levels in patients with CKD. [ABSTRACT FROM AUTHOR]

Background: Uremic toxins accumulate in renal tissues and cells due to chronic kidney disease (CKD). Abnormalities in nicotinamide adenine dinucleotide (NAD +) metabolism lead to the progression of CKD. NAD + metabolites, such as N-methyl-2-pyridone-5-carboxamide (N-Me-2PY) and N-methyl-4-pyridone-5-carboxamide (N-Me-4PY), have been recognized as uremic toxins. However, no reports have validated whether they are actually harmful to the body. Therefore, we focused on the structural similarity of these metabolites to the anti-fibrotic drug pirfenidone and evaluated their effects on renal fibrosis. Methods: Each NAD + metabolite was treated with TGFβ1 to kidney fibroblasts or tubular epithelial cells, and quantitative RT-PCR and Western blot analysis were conducted. N-Me-2PY was orally administered to a ligated murine kidney fibrosis model (UUO) to evaluate its anti-fibrotic and toxic effects on the body. Results: N-Me-2PY, N-Me-4PY, and nicotinamide N-oxide (NNO) inhibited TGFβ1-induced fibrosis and inflammatory gene expression in kidney fibroblasts. N-Me-2PY strongly suppressed the expression of types I and III collagen, αSMA, and IL-6. N-Me-2PY also suppressed TGFβ1-induced type I collagen and IL-6 expression in renal tubular epithelial cells. No toxic effect was observed with N-Me-2PY treatment, while attenuating renal fibrosis and tubular dilation in UUO mice. Suppression of various fibrosis- and inflammation-related genes was also observed. N-Me-2PY did not inhibit TGFβ1-induced Smad3 phosphorylation but inhibited Akt phosphorylation, suggesting that N-Me-2PY exerts anti-fibrotic and anti-inflammatory effects through Akt inhibition, similar to pirfenidone. Conclusions: NAD + metabolites, such as N-Me-2PY, are not uremic toxins but are potential therapeutic agents that have anti-fibrotic effects in CKD. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) significantly increases cardiovascular risk and mortality, and the accumulation of uremic toxins in the circulation upon kidney failure contributes to this increased risk. We thus performed a screening for potential novel mediators of reduced cardiovascular health starting from dialysate obtained after hemodialysis of patients with CKD. The dialysate was gradually fractionated to increased purity using orthogonal chromatography steps, with each fraction screened for a potential negative impact on the metabolic activity of cardiomyocytes using a high-throughput MTT-assay, until ultimately a highly purified fraction with strong effects on cardiomyocyte health was retained. Mass spectrometry and nuclear magnetic resonance identified the metabolite mycophenolic acid-β-glucuronide (MPA-G) as a responsible substance. MPA-G is the main metabolite from the immunosuppressive agent MPA that is supplied in the form of mycophenolate mofetil (MMF) to patients in preparation for and after transplantation or for treatment of autoimmune and non-transplant kidney diseases. The adverse effect of MPA-G on cardiomyocytes was confirmed in vitro, reducing the overall metabolic activity and cellular respiration while increasing mitochondrial reactive oxygen species production in cardiomyocytes at concentrations detected in MMF-treated patients with failing kidney function. This study draws attention to the potential adverse effects of long-term high MMF dosing, specifically in patients with severely reduced kidney function already displaying a highly increased cardiovascular risk.

Chronic kidney disease (CKD) involves progressive renal fibrosis, which gradually reduces kidney function and often causes various complications in extrarenal tissues. Therefore, we investigated fibrogenesis in extrarenal tissues (heart, liver, and lungs) in different experimental CKD models, such as the 5/6‐nephrectomy (5/6 Nx), unilateral ureteral obstruction (UUO), and a combination (2/3 Nx + UUO). We evaluated the degree of fibrogenesis in kidneys and extrarenal tissues by histological analysis and quantification of fibrosis‐related gene and protein expression. To elucidate the fibrosis mechanisms observed in 2/3 Nx + UUO mice, we evaluated the effect of indoxyl sulfate (IS), a typical uremic toxin accumulated in CKD, and transforming growth factor‐β (TGF‐β), a fibrosis‐related factor, on fibrosis using human hepatoma (HepG2) and RAW264.7 cells. A significant decline in renal function was observed in the 5/6 Nx and 2/3 Nx + UUO models, whereas a significant increase in renal fibrosis was observed only in the obstructed kidneys. Notable amount of fibrosis was induced in the liver and heart in the 2/3 Nx + UUO model, with the induction of macrophage infiltration and increased tissue IS and TGF‐β levels. In agreement with the results of in vivo experiments, co‐stimulation with IS, TGF‐β, and macrophage‐conditioned medium increased the expression of fibrogenic genes in HepG2 cells. We demonstrated that the 2/3 Nx + UUO model induced both loss of renal function and renal fibrosis in the earlier stages, providing a novel CKD model that induces remote organ fibrosis in a shorter time. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a non-reversible and progressive disease affecting the kidneys, significantly impacting global public health. One of the complications of chronic kidney disease is impaired intestinal barrier function, which may allow harmful products such as urea to enter the bloodstream and cause systemic inflammation. This study aimed to investigate whether supplementation with activated charcoal could reduce uremic toxins in patients with end-stage renal disease (ESRD). The study was a randomized clinical trial conducted at the Dialysis Center of al Diwaniyah Medical Hospital in the Diwaniyah Governorate. Eighty-two patients with ESRD on regular hemodialysis were enrolled, with 15 patients receiving oral supplementation with activated charcoal in addition to standard care and 13 patients receiving only standard care. Blood samples were collected at baseline and after eight weeks, and several biomarkers were measured, including estimated glomerular filtration rate (eGFR), creatinine, urea, phosphorus, albumin, and indoxyl sulfate. The results showed a significant reduction in both serum urea and serum phosphorus levels after eight weeks of oral-activated charcoal treatment. However, the other biomarkers were not affected by the treatment. In conclusion, the use of oral-activated charcoal for eight weeks in Iraqi patients undergoing maintenance hemodialysis improved urea and phosphorus levels. [ABSTRACT FROM AUTHOR]

The gut microbiota (GM) plays a vital role in human health, with increasing evidence linking its imbalance to chronic kidney disease and end-stage kidney disease. Although the exact methods underlying kidney-GM crosstalk are not fully understood, interventions targeting GM were made and lay in three aspects: diagnostic, predictive, and therapeutic interventions. While these interventions show promising results in reducing uremic toxins and inflammation, challenges remain in the form of patient-specific GM variability, potential side effects, and safety concerns. Our understanding of GMs role in kidney disease is still evolving, necessitating further research to elucidate the causal relationship and mechanistic interactions. Personalized interventions focusing on specific GM signatures could enhance patient outcomes. However, comprehensive clinical trials are needed to validate these approaches' safety, efficacy, and feasibility. [ABSTRACT FROM AUTHOR]

Adsorbing toxins from the blood to augment membrane-based hemodialysis is an active area of research. Films composed of β-cyclodextrin-co-(methacryloyloxy)ethyl phosphorylcholine (p(PMβCD-co-MPC)) with various monomer ratios were formed on magnetic nanoparticles and characterized. Surface chemistry effects on protein denaturation were evaluated and indicated that unmodified magnetic nanoparticles greatly perturbed the structure of proteins compared to coated particles. Plasma clotting assays were conducted to investigate the stability of plasma in the presence of particles, where a 2:2 monomer ratio yielded the best results for a given total surface area of particles. Total protein adsorption results revealed that modified surfaces exhibited reduced protein adsorption compared to bare particles, and pure MPC showed the lowest adsorption. Immunoblot results showed that fibrinogen, α1-antitrypsin, vitronectin, prekallikrein, antithrombin, albumin, and C3 correlated with film composition. Hemocompatibility testing with whole blood illustrated that the 1:3 ratio of CD to MPC had a negative impact on platelets, as evidenced by the increased activation, reduced response to an agonist, and reduced platelet count. Other formulations had statistically significant effects on platelet activation, but no formulation yielded apparent adverse effects on hemostasis. For the first time, p(PMβCD-co-MPC)-coated MNP were synthesized and their general hemocompatibility assessed. [ABSTRACT FROM AUTHOR]

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood–brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia–reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice. [ABSTRACT FROM AUTHOR]

Simple Summary: Dietary formulation can affect the composition of the microbes that reside in the gut and microbial products. Some microbial products are toxins that can accumulate in the systemic circulation of cats with a disturbed gut microbial community. Indoxyl sulfate, p-cresol sulfate, and trimethylamine-n-oxide are toxins produced during microbial fermentation of protein in the gut. By changing the gut microbial community, dietary protein concentration could affect the production of these toxins. The purpose of this study was to evaluate the effect of feeding healthy adult cats with foods containing variable protein concentrations for 3 months on the fecal microbiome and serum concentrations of the major gut-derived toxins. We found that cats fed a high-protein diet had increasing serum concentrations of p-cresol sulfate in the first 8 weeks before returning to baseline concentrations. Cats fed a high-protein diet also had increased diversity of the fecal microbial community and reduced relative abundance of beneficial bacteria in the Bifidobacterium genus. The purpose of this study was to evaluate the effect of feeding healthy adult cats with foods containing variable protein concentrations on the fecal microbiome and serum concentrations of the gut-derived uremic toxins indoxyl sulfate, p-cresol sulfate (pCS), and trimethylamine-n-oxide. Twenty healthy young adult cats were randomized into two groups and fed either a low-protein diet (LPD; 7.4 g/100 kcal ME) or a high-protein diet (HPD; 11.0 g/100 kcal ME) for a 12-week period. Serum uremic toxin concentrations were measured via liquid chromatography tandem mass spectrometry, and the fecal microbiome was characterized using shallow sequence shotgun metagenomics. Cats that consumed the HPD had higher pCS concentrations at 8 weeks (p = 0.028) when compared to baseline. After 12 weeks, cats fed the HPD had higher fecal alpha diversity indices at both the taxonomic and functional levels and lower fecal Bifidobacterium relative abundance compared to those cats fed the LPD. In conclusion, a change in diet and dietary protein concentration shifted the fecal microbial community and microbial function. Feeding cats a high amount of protein increased serum concentrations of the uremic toxin pCS; however, the effect was short-lived. [ABSTRACT FROM AUTHOR]

Introduction. Dysbiosis microbiota is considered as one of the consequences and impacts of high uremic toxins in patients with Chronic Kidney Disease (CKD), which can lead to an increased risk of progression and mortality. The aim of this systematic review and meta-analysis was to perform quantitative effect of microbiota modulation for estimated Glomerular Filtration Rate (eGFR), uremic toxin (total-p cresyl/total pCS), and inflammatory marker (hs-CRP) outcome among CKD patients. Methods. Article searches were conducted from PubMed, ScienceDirect, and Cochrane Library data sources from 2010-2022. Assessment of article quality follows the rules of PRISMA (Preferred Reporting Items in Systematic Review and Meta-Analysis). Only randomized controlled trial (RCT) articles investigating the effect of symbiotic, prebiotic, of probiotic for CKD were included in the analysis. Effect size quantify from Standardized Mean Difference (SMD), using a continuous random effect model and described in the forest plot model. Results. A total of 17 RCT studies with a total 867 CKD stage 1-5 subjects (440 subjects in the intervention group and 427 subjects in the control group). The intervention duration ranging from 1-12 months. The studies included had varied on methodologies, with significant heterogenicity (I296,96%, p Conclusions. The administration of probiotic/prebiotic/symbiotic supplements to CKD patients resulted in significant improvements in e-GFR and reductions in total pCS. These results suggest the potential of symbiotic, prebiotic, and probiotic supplementation to improve CKD outcome.

The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis. [ABSTRACT FROM AUTHOR]

Bisphenol A (BPA)-based materials are used in the manufacturing of hemodialyzers, including their polycarbonate (PC) housings and polysulfone (PS) membranes. As concerns for BPA's adverse health effects rise, the regulation on BPA exposure is becoming more rigorous. Therefore, BPA alternatives, such as Bisphenol S (BPS), are increasingly used. It is important to understand the patient risk of BPA and BPS exposure through dialyzer use during hemodialysis. Here, we report the bisphenol levels in extractables and leachables obtained from eight dialyzers currently on the market, including high-flux and medium cut-off membranes. A targeted liquid chromatography–mass spectrometry strategy utilizing stable isotope-labeled internal standards provided reliable data for quantitation with the standard addition method. BPA ranging from 0.43 to 32.82 µg/device and BPS ranging from 0.02 to 2.51 µg/device were detected in dialyzers made with BPA- and BPS-containing materials, except for the novel FX CorAL 120 dialyzer. BPA and BPS were also not detected in bloodline controls and cellulose-based membranes. Based on the currently established tolerable intake (6 µg/kg/day), the resulting margin of safety indicates that adverse effects are unlikely to occur in hemodialysis patients exposed to BPA and BPS quantified herein. With increasing availability of new data and information about the toxicity of BPA and BPS, the patient safety limits of BPA and BPS in those dialyzers may need a re-evaluation in the future. [ABSTRACT FROM AUTHOR]

Trimethylamine N-oxide (TMAO) is an intestinal uremic toxin molecule mainly excreted by the kidney. Therefore, the plasma TMAO concentration is significantly increased in chronic kidney disease (CKD) patients, and plasma TMAO can be cleared by dialysis. Furthermore, TMAO damage the kidney mainly through three mechanisms: oxidative stress, inflammation and endoplasmic reticulum stress. Clinical experiments have indicated that higher TMAO levels are strongly related to the elevated incidence and mortality of cardiovascular (CV) events in CKD patients. Moreover, experimental data have shown that high levels of TMAO directly aggravate atherosclerosis, thrombosis and enhance myocardial contractility, resulting in myocardial ischemia and stroke. Specially, there are currently four potential ways to reduce blood TMAO concentration or block the effect of TMAO, including reducing the intake of trimethylamine (TMA) precursors in the diet, regulating the intestinal flora to reduce TMA production, interrupting the role of flavin-dependent monooxygenase isoforms (FMOs) to reduce the generation of TMAO, and blocking the TMAO receptor protein kinase R-like endoplasmic reticulum kinase (PERK). We hope that more clinical studies and clinicians will focus on clinical treatment to reduce the concentration of TMAO and alleviate renal damage. [ABSTRACT FROM AUTHOR]

Background Expanded hemodialysis (HDx) is a new dialysis modality, but a systematic review of the clinical effects of using HDx is lacking. This systematic review and meta-analysis aimed to assess the efficacy and safety of HDx for hemodialysis (HD) patients.Methods PubMed, the Cochrane library, and EMBASE databases were systematically searched for prospective interventional studies comparing the efficacy and safety of HDx with those of high flux HD or HDF in HD patients.Results Eighteen trials including a total of 853 HD patients were enrolled. HDx increased the reduction ratio (RR) of β2-microglobulin (SMD 6.28%, 95% CI 0.83, 1.73, p = .02), κFLC (SMD 15.86%, 95% CI 6.96, 24.76, p = .0005), and λFLC (SMD 22.42%, 95% CI, 17.95, 26.88, p

Chronic kidney disease (CKD) is an increasing health care problem. About 10% of the general population is affected by CKD, representing the sixth cause of death in the world. Cardiovascular events are the main mortality cause in CKD, with a cardiovascular risk 10 times higher in these patients than the rate observed in healthy subjects. The gradual decline of the kidney leads to the accumulation of uremic solutes with a negative effect on every organ, especially on the cardiovascular system. Mammalian models, sharing structural and functional similarities with humans, have been widely used to study cardiovascular disease mechanisms and test new therapies, but many of them are rather expensive and difficult to manipulate. Over the last few decades, zebrafish has become a powerful non-mammalian model to study alterations associated with human disease. The high conservation of gene function, low cost, small size, rapid growth, and easiness of genetic manipulation are just some of the features of this experimental model. More specifically, embryonic cardiac development and physiological responses to exposure to numerous toxin substances are similar to those observed in mammals, making zebrafish an ideal model to study cardiac development, toxicity, and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Gut microbiota in interaction with intestinal host tissues influences many brain functions and microbial dysbiosis has been linked with brain disorders, such as neuropsychiatric conditions and Alzheimer's disease (AD). l-tryptophan metabolites and short-chained fatty acids (SCFA) are major messengers in the microbiota-brain axis. Aryl hydrocarbon receptors (AhR) are main targets of tryptophan metabolites in brain microvessels which possess an enriched expression of AhR protein. The Ah receptor is an evolutionarily conserved, ligand-activated transcription factor which is not only a sensor of xenobiotic toxins but also a pleiotropic regulator of both developmental processes and age-related tissue degeneration. Major microbiota-produced tryptophan metabolites involve indole derivatives, e.g., indole 3-pyruvic acid, indole 3-acetaldehyde, and indoxyl sulfate, whereas indoleamine and tryptophan 2,3-dioxygenases (IDO/TDO) of intestine host cells activate the kynurenine (KYN) pathway generating KYN metabolites, many of which are activators of AhR signaling. Chronic kidney disease (CKD) increases the serum level of indoxyl sulfate which promotes AD pathogenesis, e.g., it disrupts integrity of blood–brain barrier (BBB) and impairs cognitive functions. Activation of AhR signaling disturbs vascular homeostasis in brain; (i) it controls blood flow via the renin-angiotensin system, (ii) it inactivates endothelial nitric oxide synthase (eNOS), thus impairing NO production and vasodilatation, and (iii) it induces oxidative stress, stimulates inflammation, promotes cellular senescence, and enhances calcification of vascular walls. All these alterations are evident in cerebral amyloid angiopathy (CAA) in AD pathology. Moreover, AhR signaling can disturb circadian regulation and probably affect glymphatic flow. It seems plausible that dysbiosis of gut microbiota impairs the integrity of BBB via the activation of AhR signaling and thus aggravates AD pathology. Key messages: Dysbiosis of gut microbiota is associated with dementia and Alzheimer's disease. Tryptophan metabolites are major messengers from the gut host-microbiota to brain. Tryptophan metabolites activate aryl hydrocarbon receptor (AhR) signaling in brain. The expression of AhR protein is enriched in brain microvessels and blood-brain barrier. Tryptophan metabolites disturb brain vascular integrity via AhR signaling. Dysbiosis of gut microbiota promotes inflammation and AD pathology via AhR signaling. [ABSTRACT FROM AUTHOR]

A hallmark of chronic kidney disease is the retention of solutes that normally are eliminated by the kidneys. The current classification defines uremic toxins based on molecular weight and protein affinity. The retention of solutes is already detected in the early stages of the disease when patients are pauci-symptomatic or asymptomatic but the role of therapies to retard the loss of kidney function in patients with chronic kidney disease (e.g., modulators of the renin-angiotensin-aldosterone system, sodium-glucose cotransporter inhibitors) in reducing uremic toxins is poorly understood. Most of the research evaluating the impact of therapies to lower serum concentrations of those toxic compounds is carried out in patients with kidney failure already undergoing kidney replacement therapy. The removal of those molecules relies in physicochemical mass transfer phenomena, i.e., adsorption, diffusion, and convection. In the past 2 decades, the rise and broad adoption of blood purification strategies with enhanced convective properties, such as high-volume online hemodiafiltration and expanded hemodialysis, considerably amplified the ability to mechanically extract middle molecules (molecular weight >0.5 kDa) from the blood compartment. Nonetheless, the classification of uremic toxins has not evolved in parallel with dialysis advancements. Mounting evidence demonstrates the link between middle molecules with uremic symptoms, cardiovascular and mortality risks. An urgent need for updating the classification exists. Defining the causative relationship between specific solutes and specific clinical outcomes will promote the development of targeted therapies. In parallel, the inclusion of new pertinent dimensions to the classification like the influence of new dialysis membranes, sorbents, and intestinal chelators in the concentration of uremic toxins would improve the understanding of the pathogenesis of chronic kidney disease, setting the pace for future research in nephrology. [ABSTRACT FROM AUTHOR]

Hypertension can have its origin in early life. During pregnancy, many metabolic alterations occur in the mother that have a crucial role in fetal development. In response to maternal insults, fetal programming may occur after metabolic disturbance, resulting in programmed hypertension later in life. Maternal dietary nutrients act as metabolic substrates for various metabolic processes via nutrient-sensing signals. Different nutrient-sensing pathways that detect levels of sugars, amino acids, lipids and energy are integrated during pregnancy, while disturbed nutrient-sensing signals have a role in the developmental programming of hypertension. Metabolism-modulated metabolites and nutrient-sensing signals are promising targets for new drug discovery due to their pathogenic link to hypertension programming. Hence, in this review, we pay particular attention to the maternal nutritional insults and metabolic wastes affecting fetal programming. We then discuss the role of nutrient-sensing signals linking the disturbed metabolism to hypertension programming. This review also summarizes current evidence to give directions for future studies regarding how to prevent hypertension via reprogramming strategies, such as nutritional intervention, targeting nutrient-sensing signals, and reduction of metabolic wastes. Better prevention for hypertension may be possible with the help of novel early-life interventions that target altered metabolism. [ABSTRACT FROM AUTHOR]

Protein-bound uremic toxins, mainly indoxyl sulfate (3-INDS), p-cresol sulfate (pCS), and indole-3-acetic acid (3-IAA) but also phenol (Pol) and p-cresol (pC), are progressively accumulated during chronic kidney disease (CKD). Their accurate measurement in biomatrices is demanded for timely diagnosis and adoption of appropriate therapeutic measures. Multianalyte methods allowing the establishment of a uremic metabolite profile are still missing. Hence, the aim of this work was to develop a rapid and sensitive method based on high-performance liquid chromatography with fluorescence detection for the simultaneous quantification of Pol, 3-IAA, pC, 3-INDS, and pCS in human plasma. Separation was attained in 12 min, using a monolithic C18 column and isocratic elution with acetonitrile and phosphate buffer containing an ion-pairing reagent, at a flow rate of 2 mL min−1. Standards were prepared in plasma and quantification was performed using the background subtraction approach. LOQ values were ≤ 0.2 µg mL−1 for all analytes except for pCS (LOQ of 2 µg mL−1). The method proved to be accurate (93.5–112%) and precise (CV ≤ 14.3%). The multianalyte application of the method, associated to a reduced sample volume (50 µL), a less toxic internal standard (eugenol) in comparison to the previously applied 2,6-dimethylphenol and 4-ethylphenol, and a green extraction solvent (ethanol), resulted in the AGREE score of 0.62 which is in line with the recent trend of green and sustainable analytical chemistry. The validated method was successfully applied to the analysis of plasma samples from control subjects exhibiting normal levels of uremic toxins and CKD patients presenting significantly higher levels of 3-IAA, pC, 3-INDS, and pCS that can be further investigated as biomarkers of disease progression. [ABSTRACT FROM AUTHOR]

Disruption of the composition and structure of the gut microbiota, namely dysbiosis, dictates the pathophysiology of kidney diseases. The bidirectional kidney–gut axis is of interest in chronic kidney disease (CKD); the uremic milieu leads to intestinal dysbiosis and gut microbial metabolites and toxins implicated in the loss of kidney function and increased comorbidity burden. Considering that kidney diseases can originate in childhood or even earlier in fetal life, identification of the pathogenetic connection between gut microbiota dysbiosis and the development of pediatric renal diseases deserves more attention. This review concentrates on the pathogenic link between dysbiotic gut microbiota and pediatric renal diseases, covering CKD, kidney transplantation, hemodialysis and peritoneal dialysis, and idiopathic nephrotic syndrome. Gut microbiota-targeted therapies including dietary intervention, probiotics, prebiotics, postbiotics and fecal microbial transplantation are discussed for their potential for the treatment of pediatric renal diseases. A deeper understanding of gut microbiota in pediatric renal diseases will aid in developing innovative gut microbiota-targeted interventions for preventing or attenuating the global burden of kidney diseases. [ABSTRACT FROM AUTHOR]

Expanded hemodialysis (HDx) is a new dialysis modality, but a systematic review of the clinical effects of using HDx is lacking. This systematic review and meta-analysis aimed to assess the efficacy and safety of HDx for hemodialysis (HD) patients. PubMed, the Cochrane library, and EMBASE databases were systematically searched for prospective interventional studies comparing the efficacy and safety of HDx with those of high flux HD or HDF in HD patients. Eighteen trials including a total of 853 HD patients were enrolled. HDx increased the reduction ratio (RR) of β2-microglobulin (SMD 6.28%, 95% CI 0.83, 1.73, p =.02), κFLC (SMD 15.86%, 95% CI 6.96, 24.76, p =.0005), and λFLC (SMD 22.42%, 95% CI, 17.95, 26.88, p <.0001) compared with high flux HD. The RR of β2-microglobulin in the HDx group was lower than that in the HDF group (SMD −3.53%, 95% CI −1.16, −1.9, p <.0001). HDx increased the RRs of κFLC (SMD 1.34%, 95% CI 0.52, 2.16, p =.001) and λFLC (SMD 7.28%, 95% CI 1.08, 13.48, p =.02) compared to HDF. There was no significant difference in albumin loss into the dialysate between the HDx and HDF groups (SMD 0.35 g/session, 95% CI −2.38, 3.09, p =.8). This meta-analysis indicated that compared with high-flux HD and HDF, HDx can increase the clearance of medium and large-molecular-weight uremic toxins. And it does not increase the loss of albumin compared with HDF. [ABSTRACT FROM AUTHOR]

Background: Uremic toxins are associated with immune dysfunction and inflammation. The inadequate removal by hemodialysis (HD) of serum free light chains (FLCs) determines their accumulation. This study evaluated FLCs in HD patients, analyzing their relations with other biomarkers, such as serum high mobility group box 1 (HMGB1). Methods: FLC and HMGB1 were evaluated in a cohort of 119 HD patients. κFLC and λFLC were summated to give a combined (c) FLC concentration. Patients were followed prospectively until the end of the observation period of four years, or until the endpoint: the patient's death. Results: cFLC values in HD patients were 244.4 (197.9–273.5) mg/L. We detected a significant reduction in CD8+ cells and a decreased CD4+/CD8+ ratio. HMGB1 levels were 94.5 (55–302) pg/mL. After multivariate analysis, cFLCs correlated with β2-microglobulin and the CD4+/CD8+ ratio. Subjects with cFLC values above 263 mg/L and with sHMGB1 values < 80 pg/mL experienced a significantly faster evolution to the endpoint (mean follow-up time to progression of 27.5 and 28.5 months, respectively; p < 0.001). After an adjusted multivariate Cox analysis, cFLCs were associated with 11% increased risk of death, whereas low sHMGB1 increased this risk by 5%. Conclusions: cFLCs and HMGB1 reflect the inflammation and immune dysfunction in HD patients representing two strong and independent risk markers of mortality. [ABSTRACT FROM AUTHOR]

Introduction: Blood levels of uremic toxin, asymmetric dimethylarginine (ADMA), are strongly associated with mortality in sepsis, renal failure, and cardiovascular and renal disease patients. Methods: An extracorporeal approach to reduce pathological ADMA was developed. The dimethylarginine dimethylaminohydrolase (DDAH) was immobilized on agarose beads to prepare a cartridge. The efficacy of cartridge for ADMA lowering in blood was investigated. Results: The DDAH beads and cartridge reduced ADMA from solution or plasma. The magnitude of ADMA removal was dependent on the quantity of DDAH linked to the beads and the flow rate. When tested in association with plasmapheresis, the DDAH-cartridge was highly effective in ADMA removal from the blood and improved the arginine/ADMA ratio in a pig model. Conclusion: A new, safe, and effective extracorporeal approach to lower ADMA was developed which may have application in improving outcomes in patients with vascular complications and risk of mortality associated with high ADMA. [ABSTRACT FROM AUTHOR]

Background: Renal anemia is an important complication of chronic kidney disease (CKD). In addition to insufficient secretion of erythropoietin (EPO) and erythropoiesis disorders, the impact of eryptosis on renal anemia demands attention. However, a systemic analysis concerning the pathophysiology of eryptosis has not been expounded. Summary: The complicated conditions in CKD patients, including oxidative stress, osmotic stress, metabolic stress, accumulation of uremic toxins, and iron deficiency, affect the normal skeleton structure of red blood cells (RBCs) and disturbs ionic homeostasis, causing phosphatidylserine to translocate to the outer lobules of the RBC membrane that leads to early elimination and/or shortening of the RBC lifespan. Inadequate synthesis of RBCs cannot compensate for their accelerated destruction, thus exacerbating renal anemia. Meanwhile, EPO treatment alone will not reverse renal anemia. A variety of eryptosis inhibitors have so far been found, but evidence of their effectiveness in the treatment of CKD remains to be established. Key Messages: In this review, the pathophysiological processes and factors influencing eryptosis in CKD were elucidated. The aim of this review was to underline the importance of eryptosis in renal anemia and determine some promising research directions or possible therapeutic targets to correct anemia in CKD. [ABSTRACT FROM AUTHOR]

[Display omitted] • ZJU-X18 offer unique advantages in the removal of uremic toxins via anion-exchange. • ZJU-X18 exhibited high equilibrium sorption capacities toward uremic toxins. • ZJU-X18 maintained the removal efficiency of p CS and IS at over 95% after 5 cycles. • ZJU-X18 maintained high removal percentages for p CS and IS in the presence of human serum albumin. P -cresyl sulfate (p CS) and indoxyl sulfate (IS), a class of protein-bound uremic toxins, cannot be effectively cleared through hemodialysis treatment due to their strong binding to human serum albumin, posing a potential risk of cardiovascular disease in patients with chronic renal failure. Herein, we designed and prepared novel cationic metal–organic frameworks (MOFs), denoted as ZJU-X18, for the efficient removal of p CS and IS. A triptycene-based rigid trigonal prismatic ligand was utilized to link with Ag+ to yield a rare 4-fold interpenetrated MOF with abundant hydrophobic channels, affording high sorption capacity, excellent selectivity, and decent recyclability toward uremic toxins. Furthermore, the anion-exchange process between ZJU-X18 and uremic toxins is verified through density functional theory (DFT) calculations. This study provides a proactive example of the rational design of cationic MOFs from the perspective of reticular chemistry and demonstrates their promising application in uremia treatment. [ABSTRACT FROM AUTHOR]

Indole-3-acetic acid (IAA), a protein-bound uremic toxin, has been linked to cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study explores the influence of IAA (125 mg/kg) on cardiovascular changes in adenine sulfate-induced CKD rats. HPLC analysis revealed that IAA-exposed CKD rats had lower excretion and increased circulation of IAA compared to both CKD and IAA control groups. Moreover, echocardiography indicated that CKD rats exposed to IAA exhibited heart enlargement, thickening of the myocardium, and cardiac hypertrophy in contrast to CKD or IAA control group. Biochemical analyses supported the finding that IAA-induced CKD rats had elevated serum levels of c-Tn-I, CK-MB, and LDH; there was also evidence of oxidative stress in cardiac tissues, with a significant decrease in SOD and CAT levels, as well as an increase in MDA levels. The gene expression analysis found significant increases in ANP, BNP, β-MHC, TNF-α, IL-1β, and NF-κB levels in IAA-exposed CKD groups in contrast to the CKD or IAA control group. In addition, higher cardiac fibrosis markers, including Col-I and Col-III. The findings of this study indicate that IAA could trigger cardiovascular inflammation and fibrosis in CKD conditions. [Display omitted] [ABSTRACT FROM AUTHOR]

The gut microbiota (GM) plays a vital role in human health, with increasing evidence linking its imbalance to chronic kidney disease and end-stage kidney disease. Although the exact methods underlying kidney-GM crosstalk are not fully understood, interventions targeting GM were made and lay in three aspects: diagnostic, predictive, and therapeutic interventions. While these interventions show promising results in reducing uremic toxins and inflammation, challenges remain in the form of patient-specific GM variability, potential side effects, and safety concerns. Our understanding of GMs role in kidney disease is still evolving, necessitating further research to elucidate the causal relationship and mechanistic interactions. Personalized interventions focusing on specific GM signatures could enhance patient outcomes. However, comprehensive clinical trials are needed to validate these approaches’ safety, efficacy, and feasibility.

In chronic kidney disease (CKD), metabolic derangements resulting from the interplay between decreasing renal excretory capacity and impaired gut function contribute to accelerating disease progression and enhancing the risk of complications. To protect residual kidney function and improve quality of life in conservatively managed predialysis CKD patients, current guidelines recommend protein-restricted diets supplemented with essential amino acids (EAAs) and their ketoanalogues (KAs). In clinical studies, such an approach improved nitrogen balance and other secondary metabolic disturbances, translating to clinical benefits, mainly the delayed initiation of dialysis. There is also increasing evidence that a protein-restricted diet supplemented with KAs slows down disease progression. In the present review article, recent insights into the role of KA/EAA-supplemented protein-restricted diets in delaying CKD progression are summarized, and possible mechanistic underpinnings, such as protein carbamylation and gut dysbiosis, are elucidated. Emerging evidence suggests that lowering urea levels may reduce protein carbamylation, which might contribute to decreased morbidity and mortality. Protein restriction, alone or in combination with KA/EAA supplementation, modulates gut dysbiosis and decreases the generation of gut-derived uremic toxins associated, e.g., with cardiovascular disease, inflammation, protein energy wasting, and disease progression. Future studies are warranted to assess the effects on the gut microbiome, the generation of uremic toxins, as well as markers of carbamylation.

The purpose of this study was to evaluate the effect of feeding healthy adult cats with foods containing variable protein concentrations on the fecal microbiome and serum concentrations of the gut-derived uremic toxins indoxyl sulfate, p-cresol sulfate (pCS), and trimethylamine-n-oxide. Twenty healthy young adult cats were randomized into two groups and fed either a low-protein diet (LPD; 7.4 g/100 kcal ME) or a high-protein diet (HPD; 11.0 g/100 kcal ME) for a 12-week period. Serum uremic toxin concentrations were measured via liquid chromatography tandem mass spectrometry, and the fecal microbiome was characterized using shallow sequence shotgun metagenomics. Cats that consumed the HPD had higher pCS concentrations at 8 weeks (p = 0.028) when compared to baseline. After 12 weeks, cats fed the HPD had higher fecal alpha diversity indices at both the taxonomic and functional levels and lower fecal Bifidobacterium relative abundance compared to those cats fed the LPD. In conclusion, a change in diet and dietary protein concentration shifted the fecal microbial community and microbial function. Feeding cats a high amount of protein increased serum concentrations of the uremic toxin pCS; however, the effect was short-lived.

Abstract Anorexia nervosa (AN), an eating disorder, is characterized by extreme weight loss and fear of weight gain. Psychosocial factors are thought to play important roles in the development and progression of AN; however, biological factors also presumably contribute to eating disorders. Recent evidence has shown that the gut microbiota plays an important role in pathogenesis of neuropsychiatric disorders including AN. In this article, we describe the possible role of the gut microbiota in the development and persistence of AN, based on the latest research works, including those of our group.

Eryptosis is the stress-induced RBC (red blood cell) death mechanism. It is known that eryptosis is largely influenced by plasma and blood composition, and that it is accelerated in patients affected by chronic kidney disease (CKD). The aim of this study is to evaluate the eryptosis rate in healthy RBCs treated with different concentration of IL-6, IL-1β, urea and p-cresol, comparable to plasmatic level of CKD patients, at different time points. We exposed healthy RBCs to increasing concentrations of IL-6, IL-1β, urea and p-cresol. Morphological markers of eryptosis (cell membrane scrambling, cell shrinkage and PS exposure at RBC surface) were evaluated by flow cytometric analyses. The cytotoxic effect of cytokines and uremic toxins were analyzed in vitro on healthy RBCs at 4, 8 and 24 h. Morphology of treated RBCs was dramatically deranged, and the average cell volume was significantly higher in RBCs exposed to higher concentration of all molecules (all, p < 0.001). Furthermore, healthy RBCs incubated with each molecules demonstrated a significant increase in eryptosis. Cytofluorimetric analysis of eryptosis highlighted significantly higher cell death rate in RBCs incubated with a higher concentration of both cytokines compared with RBCs incubated with a lower concentration (all, p < 0.05). In conclusion, our data show that cytokines and uremic toxins have a harmful effect on RBCs viability and trigger eryptosis. Further studies are necessary to validate these results in vivo and to associate abnormal eryptosis with cytokine levels in CKD patients. The eryptosis pathway could, moreover, become a new promising target for anemia management in CKD patients. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) shows a high prevalence and is characterized by progressive and irreversible loss of renal function. It is also associated with a high risk of cardiovascular disease. The CKD population often suffers from atrial fibrillation (AF), which is associated with cardiovascular and all-cause mortality. There is a pernicious bidirectional relationship between CKD and AF: renal dysfunction can help promote AF initiation and maintenance, while unmanageable AF often accelerates kidney function deterioration. Therefore, it is necessary to determine the interactive mechanisms between CKD and AF for optimal management of patients. However, due to renal function impairment and changes in the pharmacokinetics of anticoagulants, it is still elusive to formulate a normative therapeutic schedule for the AF population concomitant with CKD especially those with end-stage kidney failure. This review describes the possible molecular mechanisms linking CKD to AF and existing therapeutic options. [ABSTRACT FROM AUTHOR]

Adsorbing toxins from the blood to augment membrane-based hemodialysis is an active area of research. Films composed of β-cyclodextrin-co-(methacryloyloxy)ethyl phosphorylcholine (p(PMβCD-co-MPC)) with various monomer ratios were formed on magnetic nanoparticles and characterized. Surface chemistry effects on protein denaturation were evaluated and indicated that unmodified magnetic nanoparticles greatly perturbed the structure of proteins compared to coated particles. Plasma clotting assays were conducted to investigate the stability of plasma in the presence of particles, where a 2:2 monomer ratio yielded the best results for a given total surface area of particles. Total protein adsorption results revealed that modified surfaces exhibited reduced protein adsorption compared to bare particles, and pure MPC showed the lowest adsorption. Immunoblot results showed that fibrinogen, α1-antitrypsin, vitronectin, prekallikrein, antithrombin, albumin, and C3 correlated with film composition. Hemocompatibility testing with whole blood illustrated that the 1:3 ratio of CD to MPC had a negative impact on platelets, as evidenced by the increased activation, reduced response to an agonist, and reduced platelet count. Other formulations had statistically significant effects on platelet activation, but no formulation yielded apparent adverse effects on hemostasis. For the first time, p(PMβCD-co-MPC)-coated MNP were synthesized and their general hemocompatibility assessed.

In patients with chronic kidney disease, the need for examinations using contrast media (CM) increases because of underlying diseases. Although contrast agents can affect brain cells, the blood–brain barrier (BBB) protects against brain-cell damage in vivo. However, uremia can disrupt the BBB, increasing the possibility of contrast-agent-induced brain-cell damage in patients with chronic kidney disease (CKD). ω-3 polyunsaturated fatty acids (PUFAs) have shown protective effects on various neurological disorders, including uremic brain injury. This study examined whether ω-3 PUFAs attenuate damage to the BBB caused by uremia and contrast agents in a uremic mouse model and evaluated its associated mechanisms. C57BL/6 mice (eight weeks old, male) and fat-1 mice (b6 background/eight weeks old, male) were divided into groups according to uremic induction, CM, and ω-3 PUFA administration. Uremia was induced via 24 h ischemia–reperfusion (IR) renal injury. One day after CM treatment, the brain tissue, kidney tissue, and blood were collected. The expression levels of glial fibrillary acidic protein (GFAP), claudin 5, CD31, laminin α4, and laminin α5 increased in ω-3 PUFA + CM-treated uremic mice and the brain of fat-1 + CM-treated uremic mice compared with those in the brains of CM-treated uremic mice. The pro-apoptotic protein expression decreased, whereas the anti-apoptotic proteins increased in ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with CM-treated uremic mice. In addition, the brain-expression levels of p-JNK, p-P53, and p-P38 decreased in the ω-3 PUFA + CM-treated uremic mice and fat-1 + CM-treated uremic mice compared with those in wild-type uremic mice. Our results confirm that uremic toxin and CM damage the BBB and cause brain-cell death. ω-3 PUFAs play a role in BBB protection caused by CM in uremic mice.

The composition of the gut microbiome is altered in patients with chronic kidney disease (CKD). Dysbiosis leads to decreased levels of stool organic acids (OAs) and systemic inflammation, followed by accumulation of uremic toxins (UTs) and the development of end-stage kidney disease (ESKD). We assessed the relationship between the microbiome and UT levels or the development of ESKD by comparing patients undergoing hemodialysis (HD) and those with normal renal function (NRF). This cross-sectional study recruited 41 patients undergoing HD and 38 sex- and age-matched patients with NRF, and gut microbiome, levels of plasma UTs, inflammatory markers, and stool OAs were compared. The indices of beta-diversity differed significantly between patients with NRF and those undergoing HD, and between patients undergoing HD with and without type 2 diabetes. The levels of stool total OA, inflammatory markers, and UTs differed significantly between the patients with NRF and those undergoing HD. The combined main effects of type 2 diabetes and kidney function status were accumulation of indoxyl sulfate and p-cresyl sulfate. The relative abundances of Negativicutes and Megamonas were associated with development of ESKD and with the levels of UTs, even after adjustment for factors associated with the progression of ESKD. The present study indicates that the gut environment differs between patients with NRF and those undergoing HD and between patients undergoing HD with and without type 2 diabetes. Moreover, ESKD patients with diabetes accumulate more UTs derived from the gut microbiome, which might be associated with cardio-renal diseases and poor prognosis.