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Background: Propolis possesses many bioactive compounds that could modulate the gut microbiota and reduce the production of uremic toxins in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). This clinical trial aimed to evaluate the effects of propolis on the gut microbiota profile and uremic toxin plasma levels in HD patients. These are secondary analyses from a previous double-blind, randomized clinical study, with 42 patients divided into two groups: the placebo and propolis group received 400 mg of green propolis extract/day for eight weeks. Indole-3 acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (p-CS) plasma levels were evaluated by reversed-phase liquid chromatography, and cytokines were investigated using the multiplex assay (Bio-Plex Magpix ® ). The fecal microbiota composition was analyzed in a subgroup of patients ( n = 6) using a commercial kit for fecal DNA extraction. The V4 region of the 16S rRNA gene was then amplified by the polymerase chain reaction (PCR) using short-read sequencing on the Illumina NovaSeq PE250 platform in a subgroup. Forty-one patients completed the study, 20 in the placebo group and 21 in the propolis group. There was a positive correlation between IAA and TNF-α (r = 0.53, p = 0.01), IL-2 (r = 0.66, p = 0.002), and between pCS and IL-7 (r = 0.46, p = 0.04) at the baseline. No significant changes were observed in the values of uremic toxins after the intervention. Despite not being significant, microbial evenness and observed richness increased following the propolis intervention. Counts of the Fusobacteria species showed a positive correlation with IS, while counts of Firmicutes , Lentisphaerae , and Proteobacteria phyla were negatively correlated with IS. Two months of propolis supplementation did not reduce the plasma levels of uremic toxins (IAA, IS, and p-CS) or change the fecal microbiota.

Background: Inflammation and oxidative stress lead to a high risk of cardiovascular disease in patients with chronic kidney disease (CKD). Food rich in polyphenols such as dark chocolate may be an effective strategy to mitigate inflammation and delay CKD complications, outwith sensorial pleasure promotion. The aim of this study was to evaluate the effects of dark chocolate on inflammation and oxidative stress markers in patients with CKD on hemodialysis (HD)., Methods: A clinical trial was carried out with 59 patients who were allocated into the chocolate group [40g of dark chocolate (70% cocoa) offered during HD sessions, 3×/week] or the control group with any intervention for two months. Plasma levels of the inflammatory cytokines TNF-α and IL-6 were evaluated by the ELISA method. Thiobarbituric acid reactive substances such as malondialdehyde (MDA) and LDLox levels were evaluated as lipid peroxidation markers. Routine biochemical parameters were analysed using commercial BioClin® kits., Results: Thirty-five patients completed the chocolate group (18 men, 53.0 (16) years and 31.0 (39) months on HD) and 11 in the control group (7 men, 48.0 (17.5) years and 44.0 (56.5) months on HD). Regarding the differences between the groups, the patients who received dark chocolate had reduced plasma levels of TNF-α compared to the control (p = 0.008). No significant changes were observed in the oxidative stress parameters evaluated in both groups. Routine biochemical (including phosphorus and potassium levels) and anthropometric parameters and food intake were not changed after the study period., Conclusion: The intervention with dark chocolate (70% cocoa) for two months reduced the plasma levels of TNF-α in patients with CKD on HD. In addition, it is essential to emphasise that chocolate intake did not increase the plasma levels of phosphorus and potassium in these patients. This study was registered at clinicaltrials.gov as NCT04600258., Competing Interests: Declaration of competing interest The authors declare they have no financial interests., (Copyright © 2022 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

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/m 2 ] 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/m 2 ] 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., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Gut dysbiosis is common in patients with chronic kidney disease (CKD) and is closely related to inflammatory processes. Some nutritional strategies, such as bioactive compounds present in curcumin, have been proposed as an option to modulate the gut microbiota and decrease the production of uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS) and indole-3 acetic acid (IAA)., Objective: To evaluate the effects of curcumin supplementation on uremic toxins plasma levels produced by gut microbiota in patients with CKD on hemodialysis (HD)., Methods: Randomized, double-blind trial in 28 patients [53.6 ± 13.4 years, fourteen men, BMI 26.7 ± 3.7 kg/m 2 , dialysis vintage 37.5 (12-193) months]. Fourteen patients were randomly allocated to the curcumin group and received 100 mL of orange juice with 12 g carrot and 2.5 g of turmeric and 14 patients to the control group who received the same juice but without turmeric three times per week after HD sessions for three months. IS, pCS, IAA plasma levels were measured by reverse-phase high-performance liquid chromatography RESULTS: After three months of supplementation, the curcumin group showed a significant decrease in pCS plasma levels [from 32.4 (22.1-45.9) to 25.2 (17.9-37.9) mg/L, p = 0.009], which did not occur in the control group. No statistical difference was observed in IS and IAA levels in both groups., Conclusion: The oral supplementation of curcumin for three months seems to reduce p-CS plasma levels in HD patients, suggesting a gut microbiota modulation.

Background: The aim of this study was to evaluate the effect of resistant starch (RS) enriched cookies supplementation on mRNA expression of nuclear transcription factors (nuclear erythroid 2-related factor, Nrf2; nuclear factor kappa-B, NF-κB), involved with inflammation and on uremic toxins levels produced by the gut microbiota in hemodialysis (HD) patients., Methods: A randomized, double-blind, placebo-controlled crossover study with 26 HD patients was conducted. The patients were assigned to either resistant starch enriched cookies (16 g of RS per day) or placebo cookies supplementation during the first four weeks. After the washout period, patients were supplemented again, in the form of a crossover, for another 4 weeks. Nrf2, NF-κB, and antioxidant enzymes mRNA expression were measured by rt-PCR and protein expression by western blotting assay from isolated peripheral blood mononuclear cells (PBMC). Oxidative stress and inflammatory biomarkers, as well as uremic toxins, were evaluated. Intention-to-treat analysis was performed, using the proc mixed procedure in SAS., Results: In RS group, post-treatment mean mRNA Nrf2 expression was market increased from baseline values, associated with a high expression of NQO1 protein. Besides, IS plasma levels were reduced in the RS group. No significant difference was observed in the placebo group., Conclusion: Our results suggested that resistant starch enriched cookies may be a good nutritional strategy to reduce indoxyl sulfate levels derived from the gut microbiota and also attenuate the inflammation in hemodialysis patients.

Purpose: In chronic kidney disease (CKD) patients, dysbiosis is associated with inflammation and cardiovascular risk, so many nutritional strategies are being studied to reduce these complications. Resistant starch (RS) can be considered a prebiotic that promotes many benefits, including modulation of gut microbiota which is linked to immune-modulatory effects. The aim of this study was to evaluate the effects of RS supplementation on proinflammatory cytokines in CKD patients on hemodialysis (HD)., Methods: A double-blind, placebo-controlled, randomized trial was conducted with sixteen HD patients (55.3 ± 10.05 years, body mass index (BMI) 25.9 ± 5.42 kg/m 2 , 56% men, time on dialysis 38.9 ± 29.23 months). They were allocated to the RS group (16 g RS/day) or placebo group (manioc flour). The serum concentration of ten cytokines and growth factors was detected through a multiparametric immunoassay based on XMap-labeled magnetic microbeads (Luminex Corp, USA) before and after 4 weeks with RS supplementation., Results: After RS supplementation, there was a reduction of Regulated upon Activation, Normal T-Cell Expressed and Secreted (p < 0.001), platelet-derived growth factor (two B subunits) (p = 0.014) and interferon-inducible protein 10 (IP-10) (p = 0.027). The other parameters did not change significantly., Conclusion: This preliminary result indicates that RS may contribute to a desirable profile of inflammatory markers in CKD patients.

Background: Irisin is a recently identified exercise-induced hormone that stimulates the "browning" of the white adipose tissue, at least in mice. In chronic kidney disease (CKD) patients, irisin regulation is not fully understood, and little attention has been given to the effects of exercise on irisin levels in these patients. The purpose of this study was to assess the effects of high intensity exercise on irisin plasma levels in CKD patients under hemodialysis (HD)., Methods: Fifteen HD patients (5 men, 44.4 ± 15.1 years old) were studied and served as their own controls. High intensity (single session) intradialytic strength exercises consisted of three sets of ten repetitions with four different movements in both lower limbs during 30 minutes. Blood samples were collected on different days (exercise and non-exercise day) at exactly the same time (30 and 60 minutes after the start of dialysis session). Plasma irisin levels were measured by ELISA assay and anthropometric and biochemical parameters were evaluated., Results: Irisin plasma levels were significantly reduced in both exercise day (125.0 ± 18.5 to 117.4 ± 15.0 ng/mL, p=0.02) and non-exercise day (121.5 ± 13.7 to 115.4 ± 17.2 ng/mL, p=0.02) after 60 minutes of dialysis., Conclusion: These data suggest that intense intradialytic strength exercise was unable to increase the circulating concentration of irisin in HD patients. Moreover, our data show that after one hour of dialysis session, irisin plasma levels may be reduced.

Purpose: This study aimed to evaluate the association among the expressions of pro- and anti-inflammatory nuclear factors (nuclear factor-kappaB, NF-κB and nuclear erythroid 2-related factor 2, Nrf2) and nutritional status in HD patients., Methods: This cross-sectional study included eighty-three HD patients. The peripheral blood mononuclear cells were isolated and processed for the evaluation of NF-κB and Nrf2 RNAm expression by quantitative real-time polymerase chain reaction. Muscle mass was estimated by creatinine index (CI) and percentage of body fat (%BF) by anthropometry. Seven-point subjective global assessment was also used to evaluate the nutritional status., Results: The NF-κB expression was negatively correlated with CI (r = -0.54, p = 0.0001), serum albumin (r = -0.32, p = 0.02) and %BF (r = -0.61, p = 0.001). Multiple linear regression analysis revealed that NF-κB expression was independently associated with CI (β: -0.8, p = 0.013) and %BF (β: -0.42, p = 0.04). There was no correlation among Nrf2 and anthropometric and biochemical variables., Conclusion: The classical NF-κB activation seems to be associated with poor nutritional status in HD patients; however, the exact underlying mechanisms deserve further studies.

Scope: Previous studies showed that the supplementation with Brazil nut is effective in improving Se status, reduce oxidative stress, and inflammation in hemodialysis (HD) patients. As the nutritional compounds may promote the reduction of inflammation by activation of nuclear factor E2-related factor 2 (Nrf2), the aim of this pilot study was to evaluate the effects of Brazil nut supplementation on Nrf2 activation in HD patients., Methods and Results: Thirteen HD patients received one Brazil nut supplementation per day for 3 months and were compared to 12 HD patients without supplementation. Peripheral blood mononuclear cells were isolated and processed for expression of nuclear factor kappa B, Nrf2, and, Nad(p)h: quinone oxidoreductase 1 (NQO1) by quantitative real-time PCR. Plasma malondialdehyde, C-reactive protein and IL-6 levels were measured before and after supplementation. The Nrf2 expression increased and nuclear factor kappa B expression reducedpost supplementation. In addition, the cytokines and malondialdehyde levels decreased significantly. No significant alterations were found in the control group., Conclusion: This preliminary result indicates the effectiveness of Brazil nut supplementation on human Nrf2 activation in HD patients and could be a possible explanation for the beneficial effects of this nut as a bioactive compound., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Oxidative stress and inflammation are common features and the main mediators of progression of chronic kidney disease (CKD) and its cardiovascular complications. Under normal conditions, oxidative stress activates the transcription factor, nuclear factor E2-related factor 2 (Nrf2), which is the master regulator of genes encoding antioxidant and detoxifying enzymes and related proteins. The available data on expression of Nrf2 and its key target gene products in CKD patients is limited. We therefore investigated this topic in a group of CKD patients on hemodialysis., Methods: Twenty adult hemodialysis (HD) patients (aged 54.9 ± 15.2 years) and 11 healthy individuals (aged 50.9 ± 8.0 years) were enrolled. Peripheral blood mononuclear cells (PBMC) were isolated and processed for expression of nuclear factor-κB (NF-κB), Nrf2, heme oxygenase-1 and NADPH: quinoneoxidoreductase 1 (NQO1) by quantitative real-time polymerase chain reaction and western blot analysis. Plasma malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) levels were measured., Results: Peripheral blood mononuclear cells from HD patients had significantly lower NQO1 and Nrf2 mRNA expressions (0.58 ± 0.35 vs. 1.13 ± 0.64, p = 0.005), and significantly higher NF-κB expression (2.18 ± 0.8 vs. 1.04 ± 0.22, p = 0.0001) compared to the healthy individuals. The NF-κB expression was inversely correlated with Nrf2 levels (r = -0.54, p < 0.01) in CKD patients. Plasma MDA and TNF-α levels were significantly higher in CKD patients than in the healthy individuals., Conclusions: Up-regulation of NFκB in the CKD patients' PBMC is coupled to down-regulation of Nrf2 and NQO1 expression. These observations are consistent with recent findings in CKD animals and point to the contribution of the impaired Nrf2 system in the pathogenesis of oxidative stress and inflammation in hemodialysis patients.

Introduction: Iron supplementation is one of the recommendations found in patients with chronic kidney disease (CKD), however, an overload of this mineral can contribute to oxidative stress, a condition closely related to the cardiovascular risk in these patients, as well as disease progression., Objective: The objective of this study was to investigate whether ferritin levels are associated with oxidative stress marker MDA in patients on hemodialysis (HD)., Methods: Twenty HD patients (55.0 ± 15.2 years, time of dialysis 76.5 ± 46.3 months, BMI 23.6 ± 3.0 kg/m2) were compared with 11 healthy subjects (50.9 ± 8.0 years, BMI 23.8 ± 1.9 kg/m2). Malondialdehyde (MDA) was measured by reaction with thiobarbituric acid and routine biochemical data were obtained from medical records., Results: MDA levels were significantly higher in HD patients compared to the control group (13.2 ± 5.3 nmol/mL vs. 5.1 ± 2.7nmol/mL, p < 0.01). Twelve patients (60%) had ferritin values greater than the 500 ng/mL and there was a positive correlation between ferritin and MDA in HD (r = 0.66, p = 0.005, n = 17) patients., Conclusion: The excess iron stores in HD patients results in increased lipid peroxidation, and consequently contributes to increased oxidative stress in these patients.