Design and rationale for an open-label, randomized, controlled pilot trial to evaluate the changes in blood uremic toxins in patients with chronic kidney disease by dietary therapy with sake lees.

BACKGROUND: Patients with chronic kidney disease (CKD) reportedly show dysbiosis, which is the imbalance of gut microbiome. Dysbiosis increases the uremic toxin level in the intestine, and uremic toxins transfer into the blood, causing CKD progression. Sake lees, a traditional Japanese fermented food, may help reduce uremic toxins by altering the gut microbiome. Additionally, D-alanine, which is present in sake lees, may have a renoprotective effect. The present pilot study aims to evaluate the effect of adding sake lees to the standard CKD dietary therapy in reducing blood uremic toxins. METHODS: This pilot study is a single-center, open-label, randomized controlled trial. Twenty-four patients with CKD will be enrolled and allocated 1:1 to the intervention and control groups. The intervention group will receive standard CKD dietary therapy with an additional intake of 50 g of sake lees per day for 8 weeks, whereas the control group will only receive standard CKD dietary therapy. The primary endpoint is the change in serum indoxyl sulfate after 8 weeks. The secondary endpoint is the plasma D-alanine and fecal microbiome changes. CONCLUSION: This pilot study provides insight into the development of a new diet focused on gut microbiome and D-amino acids in patients with CKD. CLINICAL TRIAL REGISTRATION: This protocol was approved by the Clinical Trial Review Board of Kanazawa University Hospital on October 27, 2022 (2022-001 [6139]) and available to the public on the website of the Japan Registry of Clinical Trials on November 22, 2022 (jRCT1040220095).

Uremic toxins levels from the gut microbiota seem not to be altered by physical exercise in hemodialysis patients.

PURPOSE: Regular physical exercise may result in many benefits to patients with chronic kidney disease (CKD) on hemodialysis (HD), including gut microbiota modulation and solute removal. The study aimed to evaluate the effects of two programs of intradialytic exercises on uremic toxins plasma levels in HD patients. METHODS: In experiment 1, twenty HD patients [12 men, 44.1 ± 8.9 years, BMI of 23.4 ± 2.4 kg/m2] were randomized into two groups: Aerobic exercise group (AEG, n = 11) that performed aerobic exercise on an adapted exercise bike three times a week for three months (36 sessions) and Control group (CG, n = 9). In experiment 2, twenty-six HD patients [19 men, 47.6 ± 11.0 years, BMI of 25.9 ± 3.6 kg/m2] were randomized into Resistance exercise group (REG, n = 14) that performed a resistance exercise program (using elastic bands and ankle cuffs with both lower limbs) monitored three times a week, during six months (72 sessions) and CG (n = 12). P-cresyl sulfate (p-CS), indoxyl sulfate (IS), and indol-3-acetic acid (IAA) plasma levels were determined by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: The uremic toxins plasma levels did not reduce in both exercise programs, aerobic exercise (IS: 32.7 ± 14.0 vs 33.0 ± 15.4 mg/L, p = 0.86; p-CS: 59.9 ± 39.3 vs 60.0 ± 41.2 mg/L, p = 0.99; IAA: 2233 [1488-2848] vs 2227 [1275-2824] µg/L, p = 0.72) and resistance exercise (IS: 28.3 ± 11.3 vs 29.1 ± 9.7 mg/L, p = 0.77; p-CS: 31.4 ± 21.3 vs 34.2 ± 19.8 mg/L, p = 0.63; IAA: 1628 [1330-3530] vs 2000 [971-3085] µg/L, p = 0.35) in HD patients. CONCLUSION: According to our findings, physical exercise does not appear to alter the levels of uremic toxins produced by the gut microbiota in HD patients.

Distinct Solute Removal Patterns by Similar Surface High-Flux Membranes in Haemodiafiltration: The Adsorption Point of View.

INTRODUCTION: Haemodialysis (HD) allow depuration of uraemic toxins by diffusion, convection, and adsorption. Online haemodiafiltration (HDF) treatments add high convection to enhance removal. There are no prior studies on the relationship between convection and adsorption in HD membranes. The possible benefits conferred by intrinsic adsorption on protein-bound uraemic toxins (PBUTs) removal are unknown. METHODS: Twenty-two patients underwent their second 3-days per week HD sessions with randomly selected haemodialysers (polysulfone, polymethylmethacrylate, cellulose triacetate, and polyamide copolymer) in high-flux HD and HDF. Blood samples were taken at the beginning and at the end of the treatment to assess the reduction ratio (RR) in a wide range of molecular weight uraemic toxins. A mid-range removal score (GRS) was also calculated. An elution protocol was implemented to quantify the amount of adsorbed mass (Mads) for each molecule in every dialyser. RESULTS: All synthetic membranes achieved higher RR for all toxins when used in HDF, specially the polysulfone haemodialyser, resulting in a GRS = 0.66 ± 0.06 (p < 0.001 vs. cellulose triacetate and polyamide membranes). Adsorption was slightly enhanced by convection for all membranes. The polymethylmethacrylate membrane showed expected substantial adsorption of ß2-microglobulin (MadsHDF = 3.5 ± 2.1 mg vs. MadsHD = 2.1 ± 0.9 mg, p = 0.511), whereas total protein adsorption was pronounced in the cellulose triacetate membrane (MadsHDF = 427.2 ± 207.9 mg vs. MadsHD = 274.7 ± 138.3 mg, p = 0.586) without enhanced PBUT removal. DISCUSSION/CONCLUSION: Convection improves removal and slightly increases adsorption. Adsorbed proteins do not lead to enhanced PBUTs depuration and limit membrane efficiency due to fouling. Selection of the correct membrane for convective therapies is mandatory to optimize removal efficiency.

New Strategies for the Reduction of Uremic Toxins: How Much More We Know.

The importance of uremic toxin (UTx) removal in chronic kidney disease (CKD) is an emerging topic in the literature, widely recognized over time as a strategy to slow-down the disease progression towards end-stage renal disease and, consequentely, the occurence of deleterious effects on cardiovascular (CV) system [...].

Protein-Bound Uremic Toxins Lowering Effect of Sevelamer in Pre-Dialysis Chronic Kidney Disease Patients with Hyperphosphatemia: A Randomized Controlled Trial.

P-cresyl sulfate and indoxyl sulfate are strongly associated with cardiovascular events and all-cause mortality in chronic kidney disease (CKD). This randomized controlled trial was conducted to compare the effects between sevelamer and calcium carbonate on protein-bound uremic toxins in pre-dialysis CKD patients with hyperphosphatemia. Forty pre-dialysis CKD patients with persistent hyperphosphatemia were randomly assigned to receive either 2400 mg of sevelamer daily or 1500 mg of calcium carbonate daily for 24 weeks. A significant decrease of total serum p-cresyl sulfate was observed in sevelamer therapy compared to calcium carbonate therapy (mean difference between two groups -5.61 mg/L; 95% CI -11.01 to -0.27 mg/L; p = 0.04). There was no significant difference in serum indoxyl sulfate levels (p = 0.36). Sevelamer had effects in terms of lowering fibroblast growth factor 23 (p = 0.01) and low-density lipoprotein cholesterol levels (p = 0.04). Sevelamer showed benefits in terms of retarding CKD progression. Changes in vascular stiffness were not found in this study.

Reduction of protein-bound uraemic toxins in plasma of chronic renal failure patients: A systematic review.

BACKGROUND: Protein-bound uraemic toxins (PBUTs) accumulate in patients with chronic kidney disease and impose detrimental effects on the vascular system. However, a unanimous consensus on the most optimum approach for the reduction of plasma PBUTs is still lacking. METHODS: In this systematic review, we aimed to identify the most efficient clinically available plasma PBUT reduction method reported in the literature between 1980 and 2020. The literature was screened for clinical studies describing approaches to reduce the plasma concentration of known uraemic toxins. There were no limits on the number of patients studied or on the duration or design of the studies. RESULTS: Out of 1274 identified publications, 101 studies describing therapeutic options aiming at the reduction of PBUTs in CKD patients were included in this review. We stratified the studies by the PBUTs and the duration of the analysis into acute (data from a single procedure) and longitudinal (several treatment interventions) trials. Reduction ratio (RR) was used as the measure of plasma PBUTs lowering efficiency. For indoxyl sulphate and p-cresyl sulphate, the highest RR in the acute studies was demonstrated for fractionated plasma separation, adsorption and dialysis system. In the longitudinal trials, supplementation of haemodialysis patients with AST-120 (Kremezin®) adsorbent showed the highest RR. However, no superior method for the reduction of all types of PBUTs was identified based on the published studies. CONCLUSIONS: Our study shows that there is presently no technique universally suitable for optimum reduction of all PBUTs. There is a clear need for further research in this field.

Application of Individualized PBPK Modeling of Rate Data to Evaluate the Effect of Hemodialysis on Nonrenal Clearance Pathways.

The aim of this study was to apply individualized, physiologically based pharmacokinetic modeling of 14 CO2 production rates (iPBPK-R) measured by the erythromycin breath test to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease. Twelve patients previously received 14 C-erythromycin intravenously pre- and post-hemodialysis. Serial breath samples were collected after each dose over 2 hours. Eight PBPK parameters were co-estimated across periods, whereas activity of cytochrome P450 (CYP) 3A4 clearance was independently estimated for each period. Inhibition coefficients for organic anion transporting polypeptide (OATP), P-glycoprotein, and multidrug resistance-associated protein 2 activities were also estimated. Nonrenal clearance parameter estimates were explored regarding sex differences and correlations with uremic toxins and were used in hierarchical cluster analysis (HCA). Relationships between the function of nonrenal clearance pathways and uremic toxin concentrations were explored. Mean CYP 3A4 clearance increased by 2.2% post-hemodialysis. Uptake transporter activity was highly intervariable across hemodialysis. Females had 22% and 30% higher median CYP3A4 activity than males pre- and post-hemodialysis, respectively. Exploratory HCA indicated that using both CYP3A4 and OATP activity parameters at pre- and post-hemodialysis best identifies heterogeneous patients. This is the first study to use the iPBPK-R approach to simultaneously estimate multiple in vivo nonrenal elimination pathways in individual patients with kidney disease and to assess the effect of hemodialysis.

The Prescription of Drugs That Inhibit Organic Anion Transporters 1 or 3 Is Associated with the Plasma Accumulation of Uremic Toxins in Kidney Transplant Recipients.

The renal elimination of uremic toxins (UTs) can be potentially altered by drugs that inhibit organic anion transporters 1/3 (OAT1/OAT3). The objective of the present study was to determine whether the prescription of at least one OAT1/OAT3 inhibitor was associated with the plasma accumulation of certain UTs in kidney transplant recipients. We included 403 kidney transplant recipients. For each patient, we recorded all prescription drugs known to inhibit OAT1/OAT3. Plasma levels of four UTs (trimethylamine N-oxide (TMAO), indole acetic acid (IAA), para-cresylsulfate (pCS), and indoxylsulfate (IxS) were assayed using liquid chromatography-tandem mass spectrometry. Plasma UT levels were significantly higher among patients prescribed at least one OAT inhibitor (n = 311) than among patients not prescribed any OAT inhibitors (n = 92). Multivariate analysis revealed that after adjustment for age, estimated glomerular filtration rate (eGFR), plasma level of albumin and time since transplantation, prescription of an OAT1/OAT3 inhibitor was independently associated with the plasma accumulation of pCS (adjusted odds ratio (95% confidence interval): 2.11 (1.26; 3.61]). Our results emphasize the importance of understanding the interactions between drugs and UTs and those involving UT transporters in particular.

Efficacy of Medium Cut-Off Dialyzer and Comparison with Standard High-Flux Hemodialysis.

BACKGROUND: A new medium cut-off (MCO) membranes has been designed to achieve better removal capacities for middle and large middle molecules in hemodialysis (HD) treatment. AIM: The aim of this study was to evaluate the removal efficacy of Theranova® in standard HD in comparison with standard high-flux HD. METHODS: Four HD patients (M/F 1/4) were included in 12-week observational pilot study in HD with Theranova® 400 and Theranova® 500 dialyzers. Each patient was assessed 4 times, T0 with high-flux dialyzers, T1 at 1 month, T2 at second month, and T3 at third month, by measuring pre- and post-HD samples of urea, Cr, ß2-microglobilin (ß2M), myoglobin, albumin, free light chains kappa (FLC-k), and free light chains lambda (FLC-λ). RESULTS: The data showed a higher average removal rate for all the uremic toxins with Theranova® dialyzers for ß2M, myoglobin, FLC-k, and FLC-λ (62.7, 56.9, 63.5, and 54.6%, respectively) during the 3 months. Albumin retention was observed and did not change between T0 and T3 (p = 0.379). CONCLUSION: Compared to high-flux membranes, MCO membranes show greater permeability for middle molecules in midterm report.