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Efficacy of Divinylbenzenic Resin in Removing Indoxyl Sulfate and P-Cresol Sulfate in Hemodialysis Patients: Results From an In Vitro Study and An In Vivo Pilot Trial (xuanro4-Nature 3.2).

ABSTRACT: High serum levels of microbiota-derived uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are associated with chronic kidney disease (CKD) progression and cardiovascular complications. IS and PCS cannot be efficiently removed by conventional hemodialysis (HD), due to their high binding affinity for albumin. This study evaluates the efficacy of a divinylbenzene-polyvinylpyrrolidone (DVB-PVP) cartridge and a synbiotic to reduce uremic toxins in HD patients. First, the in vitro efficacy of DVB-PVP in adsorbing IS and PCS was evaluated. Second, a randomized, placebo-controlled pilot study in HD patients was carried out to establish whether the administration of a synbiotic, either individually and in association with DVB-PVP-HD, could reduce the production of uremic toxins. In vitro data showed that DVB-PVP resin removed a mean of 56% PCS and around 54% IS, after 6 h of perfusion. While, in the in vivo study, the DVB-PVP cartridge showed its adsorbing efficacy only for IS plasma levels. The combination of synbiotic treatment with DVB-PVP HD decreased IS and PCS both at pre- and post-dialysis levels. In conclusion, this study provides the first line of evidence on the synergistic action of gut microbiota modulation and an innovative absorption-based approach in HD patients, aimed at reducing plasma levels of IS and PCS.

SUBMITTER: Rocchetti MT

PROVIDER: S-EPMC7150912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes.

Project description:Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.

| S-EPMC5696072 | biostudies-literature

p-Cresyl sulfate and indoxyl sulfate in hemodialysis patients.

Project description:Background and objectivesIndoxyl sulfate and p-cresyl sulfate are important representatives of the protein-bound uremic retention solutes. Serum levels of p-cresyl sulfate and indoxyl sulfate are linked to cardiovascular outcomes and chronic kidney disease progression, respectively. They share important features such as the albumin-binding site, low dialytic clearance, and both originate from protein fermentation. Whether serum concentrations are related is, however, not known.Design, setting, participants, & measurementsIn an observational study in 75 maintenance hemodialysis patients, we studied agreement between indoxyl sulfate and p-cresyl sulfate serum concentrations, dialytic reduction rates, and dialytic clearances. Concentrations were determined by HPLC. Dialytic clearances were determined from total spent dialysate collections. In vitro spiking experiments were performed to explore protein binding characteristics.ResultsIndoxyl sulfate and p-cresyl sulfate total serum concentrations were not related (r = 0.02, P = 0.9), whereas free serum concentrations were only moderately related (r = 0.53, P < 0.001). Indoxyl sulfate and p-cresyl sulfate share the same albumin binding site, for which they are competitive binding inhibitors. Intriguingly, indoxyl sulfate and p-cresyl sulfate reduction rates (r = 0.91, P < 0.001) and dialytic clearances (r = 0.97, P < 0.001) correlated tightly.ConclusionsIndoxyl sulfate and p-cresyl sulfate serum concentrations are not associated, suggesting different metabolic pathways. Indoxyl sulfate and p-cresyl sulfate are both valid markers to monitor behavior of protein-bound solutes during dialysis. Finally, they are competitive binding inhibitors for the same albumin binding site.

| S-EPMC2798868 | biostudies-literature

The fecal microbiome and serum concentrations of indoxyl sulfate and p-cresol sulfate in cats with chronic kidney disease.

Project description:BACKGROUND:Intestinal dysbiosis has been documented in humans with chronic kidney disease (CKD) and is thought to contribute to production of the uremic toxins indoxyl sulfate (IS) and p-cresol sulfate (pCS). Characteristics of the fecal microbiome in cats with CKD and correlation to serum concentrations of uremic toxins are unknown. OBJECTIVES:To characterize the fecal microbiome and measure serum IS and pCS concentrations of cats with CKD in comparison to healthy older cats. ANIMALS:Thirty client-owned cats with CKD (International Renal Interest Society stages 2-4) and 11 older (?8 years) healthy control cats. METHODS:Prospective, cross-sectional study. Fecal samples were analyzed by sequencing of 16S rRNA genes and Escherichia coli quantitative PCR (qPCR). Serum concentrations of IS and pCS measured using liquid chromatography tandem mass spectrometry. RESULTS:Cats with CKD had significantly decreased fecal bacterial diversity and richness. Escherichia coli qPCR showed no significant difference in bacteria count between control and CKD cats. Cats with stage 2 (P?=?.01) and stages 3 and 4 (P?=?.0006) CKD had significantly higher serum IS concentrations compared to control cats. No significant difference found between stage 2 and stages 3 and 4 CKD. The pCS concentrations were not significantly different between CKD cats and control cats. CONCLUSIONS AND CLINICAL IMPORTANCE:Decreased fecal microbiome diversity and richness is associated with CKD in cats. Indoxyl sulfate concentration is significantly increased with CKD, and cats with stage 2 CKD may suffer from a similar uremic toxin burden as do cats with later stage disease.

| S-EPMC6430892 | biostudies-literature

The relationship of indoxyl sulfate and p-cresyl sulfate with target cardiovascular proteins in hemodialysis patients.

Project description:Protein-bound uremic toxins (Indoxyl sulfate [IS] and p-cresyl sulfate [PCS]) are both associated with cardiovascular (CV) and all-cause mortality in subjects with chronic kidney disease (CKD). Possible mechanisms have not been elucidated. In hemodialysis patients, we investigated the relationship between the free form of IS and PCS and 181 CV-related proteins. First, IS or PCS concentrations were checked, and high levels were associated with an increased risk of acute coronary syndrome (ACS) in 333 stable HD patients. CV proteins were further quantified by a proximity extension assay. We examined associations between the free form protein-bound uremic toxins and the quantified proteins with correction for multiple testing in the discovery process. In the second step, the independent association was evaluated by multivariable-adjusted models. We rank the CV proteins related to protein-bound uremic toxins by bootstrapped confidence intervals and ascending p-value. Six proteins (signaling lymphocytic activation molecule family member 5, complement component C1q receptor, C-C motif chemokine 15 [CCL15], bleomycin hydrolase, perlecan, and cluster of differentiation 166 antigen) were negatively associated with IS. Fibroblast growth factor 23 [FGF23] was the only CV protein positively associated with IS. Three proteins (complement component C1q receptor, CCL15, and interleukin-1 receptor-like 2) were negatively associated with PCS. Similar findings were obtained after adjusting for classical CV risk factors. However, only higher levels of FGF23 was related to increased risk of ACS. In conclusion, IS and PCS were associated with several CV-related proteins involved in endothelial barrier function, complement system, cell adhesion, phosphate homeostasis, and inflammation. Multiplex proteomics seems to be a promising way to discover novel pathophysiology of the uremic toxin.

| S-EPMC7884394 | biostudies-literature

Preliminary evaluation of fecal fatty acid concentrations in cats with chronic kidney disease and correlation with indoxyl sulfate and p-cresol sulfate.

Project description:BackgroundStraight- and branched-chain (BCFA) short-chain fatty acids (SCFAs) are produced by colonic microbiota and have both beneficial and deleterious effects in humans with chronic kidney disease (CKD). Fecal SCFAs in cats with CKD have not been described.ObjectiveTo characterize fecal SCFA concentrations in cats with CKD as compared to healthy geriatric cats and correlate SCFA to serum indoxyl sulfate (IS) and p-cresol sulfate (pCS) concentrations.AnimalsTwenty-eight cats with CKD (International Renal Interest Society [IRIS] stages 2, 3, and 4) and 11 older (≥ 8 years) healthy geriatric cats.MethodsProspective, cross-sectional study. Voided feces were analyzed using stable isotope dilution gas chromatography-mass spectrometry to determine fecal concentrations of SCFAs. Serum concentrations of IS and pCS were measured using liquid chromatography tandem mass spectrometry.ResultsFecal isovaleric acid concentrations were significantly higher in CKD cats(P = .02) Cats with IRIS CKD stage 3 and 4 had significantly higher fecal isovaleric acid concentrations compared to healthy geriatric cats (P = .03), but not compared to IRIS CKD stage 2 cats. Total fecal concentrations of BCFAs were found to correlate weakly with serum creatinine concentration (rho, 0.33; P = .05), blood urea nitrogen concentration (rho, 0.40; P = .01), and pCS concentration (rho, 0.35; P = .04).Conclusions and clinical importanceFecal isovaleric acid concentrations were higher in CKD cats, particularly in late stage disease, compared to healthy geriatric cats. Fecal BCFA concentrations correlated with pCS and were higher in cats with muscle wasting, providing evidence for malassimilation of protein in CKD cats.

| S-EPMC6979089 | biostudies-literature

Serum total indoxyl sulfate and clinical outcomes in hemodialysis patients: results from the Japan Dialysis Outcomes and Practice Patterns Study.

Project description:BackgroundUremic toxins are associated with various chronic kidney disease-related comorbidities. Indoxyl sulfate (IS), a protein-bound uremic toxin, reacts with vasculature, accelerating atherosclerosis and/or vascular calcification in animal models. Few studies have examined the relationship of IS with clinical outcomes in a large cohort of hemodialysis (HD) patients.MethodsWe included 1170 HD patients from the Japan Dialysis Outcomes and Practice Patterns Study Phase 5 (2012-15). We evaluated the associations of serum total IS (tIS) levels with all-cause mortality and clinical outcomes including cardiovascular (CV)-, infectious- and malignancy-caused events using Cox regressions.ResultsThe median (interquartile range) serum tIS level at baseline was 31.6 μg/mL (22.6-42.0). Serum tIS level was positively associated with dialysis vintage. Median follow-up was 2.8 years (range: 0.01-2.9). We observed 174 deaths (14.9%; crude rate, 0.06/year). Serum tIS level was positively associated with all-cause mortality [adjusted hazard ratio per 10 μg/mL higher, 1.16; 95% confidence interval (CI) 1.04-1.28]. Association with cause-specific death or hospitalization events, per 10 μg/mL higher serum tIS level, was 1.18 (95% CI 1.04-1.34) for infectious events, 1.08 (95% CI 0.97-1.20) for CV events and 1.02 (95% CI 0.87-1.21) for malignancy events after adjusting for covariates including several nutritional markers.ConclusionsIn a large cohort study of HD patients, serum tIS level was positively associated with all-cause mortality and infectious events.

| S-EPMC8023193 | biostudies-literature

Indoxyl Sulfate Mediates the Low Inducibility of the NLRP3 Inflammasome in Hemodialysis Patients.

Project description:The NLRP3 inflammasome is responsible for the maturation of caspase-1 and interleukin-1β (IL-1β). Despite the study about basal activity of the NLRP3 inflammasome in hemodialysis (HD) patients, little is known about its inducibility in the milieu of uremia. Peripheral blood mononuclear cells (PBMCs) isolated from 11 HD patients and 14 volunteers without a history of chronic kidney disease, as well as macrophages with or without the uremic toxin indoxyl sulfate (IS) pretreatment, underwent canonical NLRP3 inflammasome induction. Despite the high plasma levels of IL-1β in HD patients, caspase-1 and IL-1β in the PBMCs of HD patients remained predominantly immature and were not secreted in response to the canonical stimulus. In addition, while IS alone facilitated the inflammasome-independent secretion of IL-1β from macrophages, IS exposure before induction reduced the inducibility of the NLRP3 inflammasome, characterized by insufficient maturation of caspase-1. The low expression of inflammasome components, which was observed in both IS-pretreated cells and the PBMCs of HD patients, was probably responsible for the low inducibility.

| S-EPMC7825677 | biostudies-literature

Indoxyl sulfate- and P-cresol-induced monocyte adhesion and migration is mediated by integrin-linked kinase-dependent podosome formation.

Project description:Cardiovascular disease is an important cause of death in patients with chronic kidney disease (CKD). Protein-bound uremic toxins, such as p-cresyl and indoxyl sulfate (IS), are poorly removed during hemodialysis, leading to vascular endothelial dysfunction and leukocyte extravasation. These processes can be related to dynamic adhesion structures called podosomes. Several studies have indicated the role of integrin-linked kinase (ILK) in the accumulation of integrin-associated proteins in podosomes. Here, we investigated the involvement of ILK and podosome formation in the adhesion and extravasation of monocytes under p-cresol (pc) and IS exposure. Incubation of THP-1 human monocyte cells with these toxins upregulated ILK kinase activity. Together, both toxins increased cell adhesion, podosome formation, extracellular matrix degradation, and migration of THP-1 cells, whereas ILK depletion with specific small interfering RNAs suppressed these processes. Interestingly, F-actin colocalized with cortactin in podosome cores, while ILK was colocalized in podosome rings under toxin stimulation. Podosome Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP) and AKT protein depletion demonstrated that monocyte adhesion depends on podosome formation and that the ILK/AKT signaling pathway is involved in these processes. Ex vivo experiments showed that both toxins induced adhesion and podosome formation in leukocytes from wild-type mice, whereas these effects were not observed in leukocytes of conditional ILK-knockdown animals. In summary, under pc and IS stimulation, monocytes increase podosome formation and transmigratory capacity through an ILK/AKT signaling pathway-dependent mechanism, which could lead to vascular injury. Therefore, ILK could be a potential therapeutic target for the treatment of vascular damage associated with CKD.

| S-EPMC8980039 | biostudies-literature

Effects of Sevelamer Hydrochloride on Uremic Toxins Serum Indoxyl Sulfate and P-Cresyl Sulfate in Hemodialysis Patients.

Project description:Beside the phosphate binding effect, non-calcium non-aluminum phosphate binder, namely sevelamer hydrochloride (SH), has many other effects in dialysis patients. It can absorb many other compounds, decrease low-density lipoprotein cholesterol (LDL-C) level, and attenuate the progression of vascular calcification; it has been reported to have anti-inflammatory effect. However, it is not clear whether it has any effect on uremic toxins, i.e. serum indoxyl sulfate (IS) and p-cresyl sulfate, (PCS) in hemodialysis (HD) patients. This study was carried out to appraise the effect of sevelamer on serum IS and PCS in HD patients.Five adult HD patients from a single medical center were enrolled in this study; these patients were treated with 800 mg of sevelamer thrice per day for 3 months; a series of biochemical parameters, serum IS and PCS were monitored concurrently.There was a significant reduction in the mean level of phosphate from 7.20 ± 0.70 mg/dL (mean ± SD) before treatment to 5.40 ± 0.50 mg/dL (mean ± SD) after treatment, total cholesterol from 151.00 ± 37.40 mg/dL (mean ± SD) before treatment to 119.20 ± 29.40 mg/dL (mean ± SD) after treatment, and PCS from 31.30 ± 10.60 mg/L (mean ± SD) before treatment to 19.70 ± 10.50 mg/L (mean ± SD) after treatment. On the contrary, this treatment had no effect on IS.A statistically significant reduction of serum phosphate and PCS in HD patients treated with SH suggests that beside the action of lowering serum phosphate, sevelamer may have an important role in the treatment of uremic syndrome by decreasing the uremic toxin.

| S-EPMC5544481 | biostudies-other

Lactobacillus salivarius BP121 prevents cisplatin‑induced acute kidney injury by inhibition of uremic toxins such as indoxyl sulfate and p‑cresol sulfate via alleviating dysbiosis.

Project description:The gut microbiota is important for maintaining the integrity of the intestinal barrier, promoting immunological tolerance and carrying out metabolic activities that have not evolved in hosts. Intestinal dysbiosis is associated with chronic kidney disease and probiotic supplementation has been shown to be beneficial. However, it is not known whether gut microorganisms‑specifically, lactic acid bacteria (LAB) can protect against acute kidney injury (AKI). To address this issue, the present study investigated the effects of Lactobacillus salivarius BP121, an intestinal LAB isolated from the feces of newborns, in a rat model of cisplatin‑induced AKI and also in Caco‑2 human intestinal epithelial cells. BP121 prevented cisplatin‑induced AKI in rats, as demonstrated by decreases in inflammation and oxidative stress in kidney tissue and in serum levels of uremic toxins such as indoxyl sulfate (IS) and p‑cresol sulfate (PCS). BP121 also reduced intestinal permeability, as determined using fluorescein isothiocyanate‑dextran by immunohistochemical detection of tight junction (TJ) proteins such as zona occludens‑1 and occludin. The abundance of Lactobacillus spp., which are beneficial intestinal flora, was increased by BP121; this was accompanied by an increase in the concentrations of short‑chain fatty acids in feces. Additionally, H2O2‑induced TJ protein damage was reduced in Caco‑2 cells treated with BP121 culture supernatant, an effect that was reversed by the 5' AMP‑activated protein kinase (AMPK) inhibitor Compound C and Toll‑like receptor (TLR)4 inhibitor TLR4‑IN‑C34. In conclusion, this study demonstrated that L. salivarius BP121 protects against cisplatin‑induced AKI by decreasing inflammation and oxidative stress and this renoprotective effect is partially mediated by modulating the gut environment and thereby suppressing IS and PCS production as well as by regulating AMPK and TLR4 dependent TJ assembly.

| S-EPMC7053870 | biostudies-literature

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