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It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite’s effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies. Clinical trial NCT00360399 “Predictors of Antidepressant Treatment Response: The Emory CIDAR” https://clinicaltrials.gov/ct2/show/NCT00360399 .

Home hemodialysis, despite its recognized clinical benefits such as improved cardiac health and enhanced quality of life, remains underutilized worldwide. This study aims to evaluate the efficacy of home hemodialysis within slow daily dialysis programs, employing the Physidia S3 monitor. A prospective trial was conducted with 16 stable patients suffering from end-stage kidney disease and undergoing home hemodialysis. The study assessed the efficiency of slow daily short treatment dialysis using diverse criteria, including percent reduction, effective clearances, and solute mass removal, across a broad spectrum of uremic compounds, including sodium. Controlled sessions were implemented to replicate daily home treatment conditions. Selecting urea and ß2M as key biomarkers due to their associations with patient outcomes, our study achieved a standardized weekly Kt/V of 2.26 [1.99–2.70] and estimated kidney urea clearance of 11.4 [10.9–12.4] mL/min. ß2M mass removal per session was 146 mg, extrapolating to 707 (×5) and 845 (×6) mg weekly. Additionally, the time-averaged concentration of ß2M was maintained at 19.4 mg/L. The study also identified a net sodium mass removal of 126 mmol [98–182] or 7.4 g [5.8–10.7] NaCl per session. In conclusion, our findings suggest that slow daily, short treatment time, high flux hemodialysis, augmented by enhanced internal convective clearance, represents a highly efficient renal replacement modality on a weekly basis across large molecular weight uremic compounds. Moreover, the solute dialysate saturation coefficient emerges as a promising marker in slow-flow settings.

Chronic kidney disease (CKD) is a global health burden, with uremic toxins (UTs) playing a central role in its pathophysiology. In this review, we systematically examined the evolution of UT classification from the 2003 European Uremic Toxin Work Group (EUTox) system based on molecular weight and protein-binding properties to the 2023 multidimensional framework integrating clinical outcomes, clearance technologies, and artificial intelligence. We highlighted the toxicity mechanisms of UTs across the cardiovascular, immune, and nervous systems and evaluated traditional (e.g., low-/high-flux hemodialysis) and advanced (e.g., high-cutoff dialysis and hemoadsorption) clearance strategies. Despite progress, challenges persist in toxin detection, clearance efficiency, and personalized therapy. Future directions include multi-omics-based biomarker discovery, optimized dialysis membranes, advanced adsorption technology, and AI-driven treatment personalization. This synthesis aims to bridge translational gaps and guide precision medicine in nephrology.

Online hemodiafiltration (Ol-HDF) and expanded hemodialysis (HDx; using medium cut-off dialyzers) have shown superior removal of diverse uremic toxins, particularly middle molecules and inflammatory cytokines, compared to conventional hemodialysis (HD). However, the relative efficacy of toxin removal between HDx and Ol-HDF remains unclear. This study aimed to compare these two techniques. A randomized controlled trial was conducted among thrice-weekly hemodialysis patients. Participants were randomized into either a post-dilution Ol-HDF group or an HDx group using two types of medium cut-off dialyzers (Theranova 500 ® and Elisio HX21 ® ) over 8 weeks. Efficacy was assessed by reduction ratios (RR) and pre-dialysis toxin levels. Statistical analysis used T-tests and generalized estimating equations. A total of 40 patients were enrolled (mean age 64.6 ± 12.0 years; 82.5% male; dialysis vintage 53.4 ± 38.0 months). The Ol-HDF group, with a mean convection volume of 24.7 L, had significantly higher RR for beta-2 microglobulin (82.8% vs. 74.6%; p  < 0.001), parathyroid hormone (80.4% vs. 60.6%; p  = 0.007), homocysteine (58.0% vs. 50.0%; p  = 0.009), and kappa- and lambda-free light chains (73.3% vs. 64.6%; p  = 0.0001 and 62.5% vs. 52.0%; p  = 0.0026, respectively). Pre-dialysis toxin levels at the end of the study were similar between groups. These findings highlight that Ol-HDF demonstrated superior removal of uremic toxins, while HDx was comparable to Ol-HDF in maintaining pre-dialysis levels of middle molecules and inflammatory cytokines. Trial registration This study was registered in the Thai Clinical Trials Registry (TCTR) on the first posted date 10/02/2023 with the registration number TCTR20230210004.

Because of the strain-dependent effect and the lack of simultaneous in vitro test with limited clinical data on Lacticaseibacillus rhamnosus L34 (L34) isolated from the Thai population, L34 was tested and compared with L. rhamnosus GG (LGG). The before and after test using L34 and a randomized placebo-controlled trial using placebo, L34, and LGG, for 4 weeks in patients with non-dialysis chronic kidney disease stage 3–5 (CKD) together with the in vitro experiments using indoxyl sulfate (IS, a representative uremic toxin) were performed. In comparison with the baseline, 4-week-L34 administration reduced gut-derived uremic toxins (GDUTs), except total IS, and attenuated several biomarkers, including i) systemic inflammation, as measured by cytokines and neutrophil extracellular traps using citrullinated histone 3, cell-free DNA, and fluorescent-stained nuclear morphology; ii) gut permeability defect (beta- d -glucan but not by endotoxemia); and iii) gut dysbiosis (fecal microbiome analysis). Additionally, L34-conditioned media attenuated IS-induced injuries on Caco-2 enterocytes, THP-1-derived-macrophages, and isolated neutrophils. Despite the possible different active compounds, both probiotics similarly attenuated IS-induced inflammation in vitro and in patients when compared with the placebo. In conclusion, L34 and LGG similarly attenuated systemic inflammation in patients with CKD, through the improved gut dysbiosis and anti-inflammation.

Kidney tubular damage is an important prognostic determinant in diabetic kidney disease (DKD). A vital homeostatic function of the proximal tubule is active tubular secretion of waste products via organic anion transporters (OATs), including protein-bound uremic toxins (PBUTs) that accumulate in plasma in tubular dysfunction. We here hypothesize that PBUT clearance may be a sensitive tubular function marker, and tested this in a DKD mouse model and in type 2 diabetic patients. Among the PBUTs with the highest OAT affinity (i.e., indoxyl sulfate (IS), hippuric acid (HA) and kynurenic acid (KA)), plasma concentrations were higher and urinary excretions were lower 6 and 8 months after DKD induction in mice. These parameters correlated better with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers. In patients, the clearance of IS, HA, KA and p -cresyl sulfate (PCS) was associated with urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), independent of eGFR. In multiple regression analysis, additionally adjusted for relevant risk factors for tubular injury, the clearance of IS, HA and PCS remained significantly associated with urinary NGAL. In conclusion, IS, HA, KA and PCS clearance may represent a biomarker of kidney tubular function in DKD.

Patients with end-stage renal disease have lower fasting plasma glucose and HbA1c levels, with significantly higher insulin levels. For a long time, it has been believed that this higher insulin level in renal failure is due to decreased insulin clearance caused by reduced renal function. However, here we reported that accumulation of the gut microbiota-derived uremic toxin, phenyl sulfate (PS) in the renal failure, increased insulin secretion from the pancreas by enhanced glucose-stimulated insulin secretion. Other endogenous sulfides compounds which accumulated as in the renal failure also increased glucose-stimulated insulin secretion from β-cell. With RNA-seq analyses and gene knock down, we demonstrated that insulin secretion evoked by PS was mediated by Ddah2. In addition, we also found that PS increased insulin resistance through lncRNA expression and Erk phosphorylation in the adipocytes. To confirm the relationship between PS and glucose metabolism in human, we recruited 2 clinical cohort studies (DKD and CKD) including 462 patients, and found that there was a weak negative correlation between PS and HbA1c. Because these trials did not measure fasting insulin level, we alternatively used the urinary C-peptide/creatinine ratio (UCPCR) as an indicator of insulin resistance. We found that PS may induce insulin resistance in patients with eGFR < 60 mL/min/1.73 m 2 . These data suggest that the accumulation of uremic toxins modulates glucose metabolism and induced insulin resistance in CKD and DKD patients. Considering HbA1c as a reflection of chronic hyperglycemia and UCPCR as a reflection of chronic hyperinsulinemia, our findings indicate that PS is negatively associated with hyperglycemia independent of CKD, and positively associated with hyperinsulinemia in DKD patients.

This prospective cohort study investigated the kidney clearance of protein-bound uremic toxins (PBUTs)-specifically, indole sulfate (IS), p-cresol sulfate (pCS), and indole-3-acetic acid (IAA)-across various stages of chronic kidney disease (CKD) stages and their associations with adverse clinical outcomes. From July 2018 to December 2020, 186 non-dialysis CKD patients were enrolled and followed until June 2025. Serum and 24-hour (24 h) urine PBUT levels were measured, and kidney clearances were analyzed. The findings indicated a decrease in the 24 h kidney clearances of IS (Cis), pCS (Cpcs), and IAA (Ciaa) corresponding with a reduction in glomerular filtration rate (GFR) across the CKD stages. For instance, the clearance of indoxyl sulfate was observed to decline from 26.7 mL/min in stage 1 to 2.2 mL/min in stage 5. PBUT clearances and fractional clearances were generally unaffected by 24 h urinary protein levels, with the exception of fractional clearance of IAA. Elevated levels of Cis and Ciaa were independently correlated with decreased risks of renal outcomes (IS: HR 0.964; IAA: HR 0.941) and hospitalization (IS: HR 0.984; IAA: HR 0.961). The study concluded that the 24 h kidney clearances of IS and IAA are independently associated with renal adverse outcomes and hospitalization, with minimal influence from urinary protein excretion.

The current study outlines the removal of Creatinine, p -Cresol sulfate, and Hippuric acid from simulated blood using three new granules: Fe-BTC@Sephadex, Cu-BTC@Sephadex, and Co-BTC@Sephadex. Beads were used to adsorbed toxic chemicals, and the effects of various experimental parameters were examined in the adsorption optimization process. The framework’s adsorption isotherms were explained by the application of the Freundlich and Langmuir models. The kinetics of adsorption is represented by a pseudo-first and second-order equation. The morphology and structure of the Fe-BTC@ Sephadex, Co-BTC@ Sephadex, and Cu-BTC@Sephadex beads were investigated using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and X-ray diffraction (XRD). The adsorption capacities for creatinine were 545.69, 339.76, and 189.88 mg/g for Fe-BTC@ Sephadex, Cu-BTC@ Sephadex, and Co-BTC@ Sephadex, respectively, according to the results; the corresponding adsorption capacities for hippuric acid were 323.78, 206.79, and 68.059 mg/g, and the maximum adsorption capacities for p -Cresol sulfate were 122.65, 71.268, and 40.347 mg/g, respectively. These were, in fact, promising findings that have implications for an industrial-scale transportable artificial kidney.

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