Effects of dietary compounds on nuclear factor erythroid 2-related factor 2 (Nrf2) modulation in chronic kidney disease: a systematic review of clinical trials.

Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important transcription factor that activates antioxidant genes and increases detoxifying enzymes. Studies have shown that dietary compounds can activate the Nrf2 expression and improve the antioxidant response in patients with exacerbated oxidative stress, such as chronic kidney disease (CKD). We aimed to evaluate the efficacy of nutritional interventions on Nrf2 expression and phase II antioxidant enzymes in clinical trials in CKD. We searched PubMed, Lilacs, Embase, Scopus, and Cochrane Library databases of published clinical trials and the Cochrane tool was used for the quality assessment of the studies included. We reported this review according to the PRISMA and it was registered in PROSPERO (42023389619). Thirty-nine studies were included in this review; nine evaluated the Nrf2 expression and three showed an increase in its expression. Twenty-three studies found an increase in the antioxidant enzyme levels, including superoxide dismutase, catalase, and glutathione peroxidase. Moreover, a high risk of bias was found in most of the studies and high heterogeneity in the designs, type, and duration of supplementation administered. These results suggest that dietary supplementations have a promising effect on the antioxidant enzyme response, however, it is recommended that further studies should be carried out.

Selenium supplementation in chronic kidney disease patients undergoing haemodialysis: a systematic review of the effects on plasma selenium, antioxidant and inflammatory markers, immunological parameters and thyroid hormones.

Selenium (Se) is a mineral with several biological functions, and studies have shown that its deficiency can be linked to many complications in patients with chronic kidney disease (CKD). This study aims to systematically review the effects of Se supplementation in patients with CKD undergoing haemodialysis (HD). This systematic review was carried out according to the PRISMA statement. Clinical trials were searched in PubMed, Lilacs, Embase, Scopus and Cochrane Library databases from inception to July 2021 and updated in July 2024. The protocol was registered on PROSPERO (CRD42021231444). Two independent reviewers performed the study screening and data extraction, and the risk of bias was evaluated using the Cochrane Collaboration tool. Thirteen studies were included in this review. Only nine studies showed results on Se levels; in all, reduced Se levels were observed before supplementation. A positive effect of supplementation on plasma Se level was demonstrated. Of the ten studies analysed, six demonstrated positive effects on antioxidant and inflammatory markers. Only one study analysed immunological parameters, showing a positive impact. From two studies that analysed thyroid hormones, only one showed positive results. All studies were classified as high risk of bias. The findings suggest that Se supplementation significantly increases plasma Se levels in these patients; however, there are still not enough studies to clarify the effects of Se supplementation on the antioxidant and inflammatory markers, immune system and thyroid hormones. Further studies are needed to elucidate the effects of Se supplementation and to provide a recommendation for patients with CKD undergoing HD.

Sulforaphane Supplementation Did Not Modulate NRF2 and NF-kB mRNA Expressions in Hemodialysis Patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have reduced expression of erythroid nuclear factor-related factor 2 (NRF2) and increased nuclear factor κB (NF-κB). "Food as medicine" has been proposed as an adjuvant therapeutic alternative in modulating these factors. No studies have investigated the effects of sulforaphane (SFN) in cruciferous vegetables on the expression of these genes in patients with CKD. OBJECTIVE: The study aimed to evaluate the effects of SFN on the expression of NRF2 and NF-κB in patients on hemodialysis (HD). DESIGN AND METHODS: A randomized, double-blind, crossover study was performed on 30 patients on regular HD. Fourteen patients were randomly allocated to the intervention group (1 sachet/day of 2.5 g containing 1% SFN extract with 0.5% myrosinase) and 16 patients to the placebo group (1 sachet/day of 2.5 g containing corn starch colored with chlorophyll) for 2 months. After a washout period of 2 months, the groups were switched. NRF2 and NF-κB mRNA expression was evaluated by real-time quantitative polymerase chain reaction, and tumor necrosis factor alpha and interleukin-6 levels were quantified by enzyme-linked immunosorbent assay. Malondialdehyde was evaluated as a marker of lipid peroxidation. RESULTS: Twenty-five patients (17 women, 55 [interquartile range = 19] years and 55 [interquartile range = 74] months on HD) completed the study. There was no significant difference concerning the expression of mRNA NRF2 (P = .915) and mRNA NF-κB (P = .806) after supplementation with SFN. There was no difference in pro-inflammatory and oxidative stress biomarkers. CONCLUSION: 150 µmol of SFN for 2 months had no antioxidant and anti-inflammatory effect in patients with CKD undergoing HD.

A normative microbiome is not restored following kidney transplantation.

Dialysis and kidney transplantation (Ktx) mitigate some of the physiological deficits in chronic kidney disease (CKD), but it remains to be determined if these mitigate microbial dysbiosis and the production of inflammatory microbial metabolites, which contribute significantly to the uraemic phenotype. We have investigated bacterial DNA signatures present in the circulation of CKD patients and those receiving a KTx. Our data are consistent with increasing dysbiosis as CKD progresses, with an accompanying increase in trimethylamine (TMA) producing pathobionts Pseudomonas and Bacillus. Notably, KTx patients displayed a significantly different microbiota compared with CKD5 patients, which surprisingly included further increase in TMA producing Bacillus and loss of salutogenic Lactobacilli. Only two genera (Viellonella and Saccharimonidales) showed significant differences in abundance following KTx that may reflect a reciprocal relationship between TMA producers and utilisers, which supersedes restoration of a normative microbiome. Our metadata analysis confirmed that TMA N-oxide (TMAO) along with one carbon metabolism had significant impact upon both inflammatory burden and the composition of the microbiome. This indicates that these metabolites are key to shaping the uraemic microbiome and might be exploited in the development of dietary intervention strategies to both mitigate the physiological deficits in CKD and enable the restoration of a more salutogenic microbiome.

Effects of Polydextrose Supplementation on Intestinal Function in Hemodialysis Patients: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVES: Intestinal constipation is a frequent complication in hemodialysis (HD) patients. Polydextrose (PDX), a nondigestible oligosaccharide, has been reported as a fermentable fiber with potential benefits. This study aimed to investigate the possible influence of PDX supplementation on intestinal function in HD patients. METHODS: This randomized, double-blind, placebo-controlled trial included 28 patients who received daily oral supplementation with 12 g of PDX or placebo (corn starch) for 2 months. ROME IV criteria were used to define constipation and questionnaires were applied to patient assessment of constipation symptoms (PAC-SYM) and their impact on the patient assessment of constipation quality of life. The Bristol scale was used to assess stool consistency. Commercial Enzyme-Linked Immuno Sorbent Assay kits were used to evaluate the interleukin-6 and tumor necrosis factor-α plasma levels. RESULTS: 25 patients completed the study; 16 in the PDX group [7 females, 48.5 years (IQR = 15.5)] and 9 in the control group [3 females, 44.0 years (IQR = 6.0)]. According to ROME IV criteria, 55% of patients were diagnosed with constipation. PAC-SYM faecal symptoms domain was reduced after 2 months of PDX supplementation (P = .004). We also observed a significant reduction in the PAC-QoL-concerns domain (P = .02). The average values for PAC-SYM and patient assessment of constipation quality of lifewere reduced significantly after intervention with PDX. There were no significant changes after the intervention period concerning biochemical variables, food intake, and inflammation markers. No adverse effects were observed during the supplementation period. CONCLUSIONS: The results of the present study suggest that short-term PDX supplementation may have favourable results on intestinal function and the quality of life of chronic kidney disease patients in HD.

Protect the Kidneys and Save the Heart Using the Concept of Food as Medicine.

Chronic kidney disease is a significant risk factor for cardiovascular disease. In addition to traditional risk factors, such as hypertension, dyslipidemia, diabetes and smoking, patients with chronic kidney disease have a uremic phenotype marked by premature aging, mitochondrial dysfunction, persistent low-grade inflammation, gut dysbiosis and oxidative stress. These complications contribute to abnormal vascular and myocardial remodeling processes, resulting in accelerated vascular calcification, cellular and organ senescence and a high risk of cardiovascular disease. Nonpharmacological strategies, such as increasing physical activity and a healthy diet, may slow the progression of kidney disease and consequently protect the heart. Thus, a deep promotion and advocacy of nutritional guidance based on scientific data is needed. This narrative review discusses how nutritional interventions may delay progressive organ damage in the kidney-heart axis.

Targeting the Gut Microbiota in Kidney Disease: The Future in Renal Nutrition and Metabolism.

There is increasing interest in the therapeutic potential of manipulating the gut microbiome of patients with chronic kidney disease (CKD). This is because there is a substantial deviation from a balanced gut microbiota profile in CKD, with many deleterious downstream effects. Nutritional interventions such as plant-based diets with reduced animal protein intake and the use of probiotics, prebiotics, and synbiotics may alter the microbiome. This article aims to briefly describe what is known about the gut microbiome in patients with CKD, factors contributing to gut dysbiosis, and outline important evidence gaps. Future potential therapies, including restoring the microbiota with food and microbiota-based and metabolomic-based therapies, are also discussed.

COVID-19 and Nutrition: Focus on Chronic Kidney Disease.

Some chronic diseases, including chronic kidney disease (CKD), may be associated with poor outcomes, including a high rate of hospitalization and death after COVID-19 infection. In addition to the vaccination program, diet intervention is essential for boosting immunity and preventing complications. A healthy diet containing bioactive compounds may help mitigate inflammatory responses and oxidative stress caused by COVID-19. In this review, we discuss dietary interventions for mitigating COVID-19 complications, including in persons with CKD, which can worsen COVID-19 symptoms and its clinical outcomes, while diet may help patients with CKD to resist the ravages of COVID-19 by improving the immune system, modulating gut dysbiosis, mitigating COVID-19 complications, and reducing hospitalization and mortality. The concept of food as medicine, also known as culinary medicine, for patients with CKD can be extrapolated to COVID-19 infection because healthy foods and nutraceuticals have the potential to exert an important antiviral, anti-inflammatory, and antioxidant role.

Planetary Health, Nutrition, and Chronic Kidney Disease: Connecting the Dots for a Sustainable Future.

The increasing consumption of ultra-processed food (UPF) and the global chain of food production have a negative impact on human health and planetary health. These foods have been replacing the consumption of nonprocessed healthy foods. This shift has not only worsened human health by increasing the risk of the development of noncommunicable diseases, but also resulted in environmental perturbations. This review aims to bring awareness of the problems caused by the industrialized food production chain, addressing the negative effects it has on the environment and human health, with special reference to chronic kidney disease (CKD). We discuss possible solutions focusing on the benefits of adopting plant-based diets with low UPF content to promote a sustainable and healthy food production and diet for patients with CKD. For a sustainable future we need to "connect the dots" of planetary health, food production, and nutrition in the context of CKD.

Food for healthier aging: power on your plate.

Inflammageing is a persistent low-level inflammatory burden that accompanies age-related dysregulation of the immune system during normative aging and within the diseasome of aging. A healthy diet containing a balanced amount of macronutrients, vitamins and minerals, adequate in calories and rich in poly(phenols), has an essential role in mitigating the effects of inflammageing and extending healthspan through modulation of the activity of a range of factors. These include transcription factors, such as nuclear factor erythroid-derived 2 related factor 2 (Nrf2) and nuclear factor-κB (NF-kB), the inflammasome and the activities of the gut microbiota. The aim of this narrative review is to discuss the potential of food to ameliorate the effects of the diseasome of aging.

The magical smell and taste: Can coffee be good to patients with cardiometabolic disease?

Coffee is a beverage consumed globally. Although few studies have indicated adverse effects, it is typically a beneficial health-promoting agent in a range of diseases, including depression, diabetes, cardiovascular disease, and obesity. Coffee is rich in caffeine, antioxidants, and phenolic compounds, which can modulate the composition of the gut microbiota and mitigate both inflammation and oxidative stress, common features of the burden of lifestyle diseases. This review will discuss the possible benefits of coffee on complications present in patients with diabetes, cardiovascular disease and chronic kidney disease, outwith the social and emotional benefits attributed to caffeine consumption.

Can Resveratrol Supplementation Reduce Uremic Toxin Plasma Levels From the Gut Microbiota in Nondialyzed Patients With Chronic Kidney Disease?

OBJECTIVES: Uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (pCS), and indole-3-acetic acid (IAA) produced by the gut microbiota are recognized as risk factors for many comorbidities, including cardiovascular diseases. Patients with chronic kidney disease (CKD) have an accumulation of these toxins, and nutritional strategies have been proposed to mitigate gut dysbiosis and, consequently, reduce these toxins. This study aimed to evaluate the effects of resveratrol supplementation on the plasma levels of IS, pCS, and IAA in nondialyzed patients with CKD. METHODS: In this placebo-controlled crossover study, twenty nondialyzed patients were randomly divided into two groups: they received either one capsule/day containing 500 mg of trans-resveratrol (63 ± 7.5 years, glomerular filtration rate [GFR]: 34 ± 14 mL/min, body mass index: 26.8 ± 5.6 kg/m2) or a placebo containing 500 mg wheat flour (62 ± 8.4 years, GFR: 34 ± 13 mL/min, body mass index: 28.6 ± 4.4 kg/m2) during 4 weeks. After 8 weeks of washout (no supplementation), another 4 weeks of supplementation with crossover was initiated. IS, IAA, and pCS plasma levels were quantified by the reverse phase high-efficiency liquid chromatography method with fluorescent detection. The mRNA expression of nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B in peripheral blood mononuclear cells was evaluated by polymerase chain reaction. C-reactive protein plasma levels were also evaluated. RESULTS: As expected, the uremic toxin levels were negatively correlated with the GFR, but no effect of trans-resveratrol supplementation was found on levels of IS, IAA, and pCS. There was a positive correlation between IS and nuclear factor erythroid 2-related factor 2 (r = 0.24, P = .03) and also between IS and C-reactive protein (r = 0.21, P = .05). CONCLUSION: Supplementation with trans-resveratrol did not reduce the plasma levels of IS, pCS, and IAA in nondialyzed patients with CKD. The interactions among uremic toxins and anti-inflammatory and proinflammatory pathways deserve more studies.

Archaea from the gut microbiota of humans: Could be linked to chronic diseases?

Archaea comprise a unique domain of organisms with distinct biochemical and genetic differences from bacteria. Methane-forming archaea, methanogens, constitute the predominant group of archaea in the human gut microbiota, with Methanobrevibacter smithii being the most prevalent. However, the effect of methanogenic archaea and their methane production on chronic disease remains controversial. As perturbation of the microbiota is a feature of chronic conditions, such as cardiovascular disease, neurodegenerative diseases and chronic kidney disease, assessing the influence of archaea could provide a new clue to mitigating adverse effects associated with dysbiosis. In this review, we will discuss the putative role of archaea in the gut microbiota in humans and the possible link to chronic diseases.

Can diet modulate trimethylamine N-oxide (TMAO) production? What do we know so far?

BACKGROUND: Trimethylamine N-oxide (TMAO) is a metabolite that has attracted attention due to its positive association with several chronic non-communicable diseases such as insulin resistance, atherosclerotic plaque formation, diabetes, cancer, heart failure, hypertension, chronic kidney disease, liver steatosis, cardiac fibrosis, endothelial injury, neural degeneration and Alzheimer's disease. TMAO production results from the fermentation by the gut microbiota of dietary nutrients such as choline and carnitine, which are transformed to trimethylamine (TMA) and converted into TMAO in the liver by flavin-containing monooxygenase 1 and 3 (FMO1 and FMO3). Considering that TMAO is involved in the development of many chronic diseases, strategies have been found to enhance a healthy gut microbiota. In this context, some studies have shown that nutrients and bioactive compounds from food can modulate the gut microbiota and possibly reduce TMAO production. OBJECTIVE: This review has as main objective to discuss the studies that demonstrated the effects of food on the reduction of this harmful metabolite. METHODS: All relevant articles until November 2020 were included. The articles were searched in Medline through PubMed. RESULTS: Both the food is eaten acutely and chronically, by altering the nature of the gut microbiota, influencing colonic TMA production. Furthermore, hepatic production of TMAO by the flavin monooxygenases in the liver may also be influenced by phenolic compounds present in foods. CONCLUSION: The evidence presented in this review shows that TMAO levels can be reduced by some bioactive compounds. However, it is crucial to notice that there is significant variation among the studies. Further clinical studies should be conducted to evaluate these dietary components' effectiveness, dose, and intervention time on TMAO levels and its precursors.

Coronavirus Disease 2019: Quick Diet and Nutrition Guide for Patients With Chronic Kidney Disease.

Considering the Covid-19 pandemic and that patients with CKD are included in a high-risk group, a quick nutrition guide for patients with CKD in all stages was developed, and it is available in Portuguese at https://bit.ly/2zfSjl0, in English at https://bit.ly/covid19ckd, in Spanish at https://bit.ly/guia enfermedad renal and in French at https://bit.ly/covid19maladierenale.

Zinc Plasma Status and Sensory Perception in Nondialysis Chronic Kidney Disease Patients.

OBJECTIVE: The aim of this study was to evaluate the association between zinc plasma levels and sensory perception in patients with chronic kidney disease (CKD). METHODS: A cross-sectional study with 21 nondialysis CKD patients (11 men, 51.1 ± 7.1 years, body mass index 27.9 ± 7.1 kg/m2, estimated glomerular filtration rate 32.7 ± 19.9 mL/min) and 22 non-CKD volunteers (10 men, 49.8 ± 8.3 years, body mass index 28.5 ± 5.4 kg/m2) was conducted. Blood samples were collected to obtain plasma for zinc analysis. Anthropometric and biochemical parameters, as well as food intake and salivary flow rate, were also evaluated. Taste sensory perception for sweet, acidic, bitter, and salty flavors was determined by the "three-drop method," with 4 concentrations of the 4 basic tastes. RESULTS: As expected, zinc plasma levels were significantly lower in CKD patients (70.1 ± 19.2ug/dL) when compared with the control group participants (123.2 ± 24.6 µg dL) (P ˂ .0001). The bitter taste perception was lower in the CKD group (p˂0.0001). Our findings showed that sensitivity to sour (P = .047), salty (P = .03), and bitter tastes was significantly lower in participants with lower zinc plasma levels. Also, bitter taste sensitivity was lower in participants with less zinc intake (P = .038). When grouping control subjects and CKD patients, significant correlations were observed between zinc plasma levels and the number of correct answers for bitter taste (r = 0.49, P = .001), number of correct answers for salty taste (r = 0.30, P = .048), and total score of correct answers (r = 0.30, P = .044). CONCLUSIONS: Reduced zinc plasma levels in nondialysis CKD patients may be associated with lower perception of bitter, sour, and salty tastes and strategies to restore these levels are crucial due many factors, including food preferences and intake.

Effects of Low Protein Diet on Nuclear Factor Erythroid 2-Related Factor 2 Gene Expression in Nondialysis Chronic Kidney Disease Patients.

OBJECTIVE(S): Low protein diets (LPD; 0.6 g/kg/day), prescribed for nondialysis chronic kidney disease (CKD) patients, have demonstrated numerous benefits. LPDs may modulate inflammation and oxidative stress through the nuclear factor erythroid 2-related factor 2 (Nrf2), which encodes antioxidant and phase II detoxifying enzymes. LPDs also inhibit or antagonize nuclear factor kB (NF-kB) activity, which orchestrates inflammatory and oxidative stress responses. The objective of this study was to evaluate the effects of LPD on Nfr2 and NF-κB messenger RNA (mRNA) expression in nondialysis CKD patients. METHODS: In this longitudinal study, a LPD was prescribed for 30 nondialysis CKD patients for 6 months. Peripheral blood mononuclear cells were isolated, and quantitative real-time polymerase chain reaction analysis was performed to evaluate Nrf2, NF-κB, and NADPH quinine oxidoreductase-1 mRNA expression. Thiobarbituric acid-reactive substance (TBARS) levels, a marker of lipid peroxidation, were also evaluated. RESULTS: (Age 55.5 ± 14.0 years; body mass index 29.1 ± 5.9 kg/m2; glomerular filtration rate 35.6 ± 12.2 mL/minute). After 6 months of nutritional intervention, Nrf2 mRNA expression increased from 0.85 (0.47-1.56) to 1.28 (0.63-2.63) nmol/mL (P = .03), and TBARS levels were significantly decreased from 1.78 (1.31-2.38) to 1.30 (1.07-2.22) nmol/mL (P = .04). NF-κB mRNA expression showed no significant difference after 6 months, but the Nrf2/NF-κB ratio was increased. CONCLUSION(S): In this study, a LPD appeared to modulate Nrf2 expression and decrease the levels of TBARS in nondialysis CKD patients. However, more studies are needed to confirm the effectiveness of LPD on the modulation of transcription factors involved with oxidative stress and inflammation in nondialysis CKD patients.

Aryl Hydrocarbon Receptor and Uremic Toxins from the Gut Microbiota in Chronic Kidney Disease Patients: Is There a Relationship between Them?

Recent studies have suggested that uremic toxins such as indoxyl sulfate (IS) and indole-3-acetic acid (IAA) from the metabolism of the gut microbiota may be involved in the inflammatory signaling pathway in chronic kidney disease (CKD) patients through the activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. The objective of this study was to investigate the possible relationship between uremic toxins (IS and IAA) and AhR protein expression in CKD patients. A cross-sectional observational study involving 17 hemodialysis (HD) [11 men, 55.5 ± 11.7 years of age, 54.0 (25.5-136.0) months of HD, body mass index (BMI) of 25.8 ± 3.8 kg/m2] and 15 non-dialysis-dependent (NDD) CKD (8 men, 54.1 ± 18.2 years of age, glomerular filtration rate of 34.8 ± 21.0 mL/min/1.73 m2, BMI of 27.4 ± 5.0 kg/m2) patients was conducted. IS and IAA levels were measured by reversed-phase high-performance liquid chromatography, and the protein expression levels of AhR and nuclear factor κ B (NF-κB) were evaluated by a Western blot assay. There was no difference in the expression of either AhR or NF-κB in the patients, and as expected, uremic toxin levels were higher in HD patients than in NDD patients. In the overall analysis, AhR protein expression was positively associated with IAA plasma levels ( r = 0.4; p = 0.03) and NF-κB protein expression ( r = 0.62; p = 0.001). Although the role of AhR in inflammation and CVD in CKD patients is far from being completely understood, the association between IAA and AhR observed in this study suggests a possible role for uremic toxins in the cell signaling pathway involved in inflammation in CKD patients.

Methyl Donor Nutrients in Chronic Kidney Disease: Impact on the Epigenetic Landscape.

Epigenetic alterations, such as those linked to DNA methylation, may potentially provide molecular explanations for complications associated with altered gene expression in illnesses, such as chronic kidney disease (CKD). Although both DNA hypo- and hypermethylation have been observed in the uremic milieu, this remains only a single aspect of the epigenetic landscape and, thus, of any biochemical dysregulation associated with CKD. Nevertheless, the role of uremia-promoting alterations on the epigenetic landscape regulating gene expression is still a novel and scarcely studied field. Although few studies have actually reported alterations of DNA methylation via methyl donor nutrient intake, emerging evidence indicates that nutritional modification of the microbiome can affect one-carbon metabolism and the capacity to methylate the genome in CKD. In this review, we discuss the nutritional modifications that may affect one-carbon metabolism and the possible impact of methyl donor nutrients on the microbiome, CKD, and its phenotype.