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.

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.

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.

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.

Probiotic Supplementation in Chronic Kidney Disease: A Double-blind, Randomized, Placebo-controlled Trial.

OBJECTIVE: The objective of the study was to evaluate the effects of probiotic supplementation on the gut microbiota profile and inflammatory markers in chronic kidney disease patients undergoing maintenance hemodialysis (HD). DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled study. Forty-six HD patients were assigned to receive 1 of 2 treatments: probiotic (n = 23; Streptococcus thermophilus, Lactobacillus acidophilus e Bifidobacterialongum, 90 billion colony-forming units per day) or placebo (n = 23) daily for 3 months. Blood and feces were collected at baseline and after intervention. The inflammatory markers (C-reactive protein and interleukin-6) were analyzed by immunoenzymatic assay (enzyme-linked immunosorbent assay). Uremic toxins plasma levels (indoxyl sulfate, p-cresyl sulfate, and indole-3-acetic acid) were obtained by Reversed-Phase High-Performance Liquid Chromatography. Routine laboratory parameters were measured by standard techniques. Fecal pH was measured by the colorimetric method, and the gut microbiota profile was assessed by Denaturing Gradient Gel Electrophoresis analysis. RESULTS: Sixteen patients remained in the probiotic group (11 men, 53.6 ± 11.0 year old, 25.3 ± 4.6 kg/m2) and 17 in the placebo group (10 men, 50.3 ± 8.5 year old, 25.2 ± 5.7 kg/m2). After probiotic supplementation there was a significant increase in serum urea (from 149.6 ± 34.2 mg/dL to 172.6 ± 45.0 mg/dL, P = .02), potassium (from 4.4 ± 0.4 mmol/L to 4.8 ± 0.4 mmol/L, P = .02), and indoxyl sulfate (from 31.2 ± 15.9 to 36.5 ± 15.0 mg/dL, P = .02). The fecal pH was reduced from 7.2 ± 0.8 to 6.5 ± 0.5 (P = .01). These parameters did not change significantly in placebo group. Changes in the percentage delta (Δ) between groups were exhibited with no statistical differences observed. The inflammatory markers and gut profile were not altered by supplementation. CONCLUSIONS: Aprobiotic supplementation failed to reduce uremic toxins and inflammatory markers. Therefore, probiotic therapy should be chosen with caution in HD patients. Further studies addressing probiotic therapy in chronic kidney disease patients are needed.

Resistant starch for modulation of gut microbiota: Promising adjuvant therapy for chronic kidney disease patients?

The gut microbiota has been extensively studied in all health science fields because its imbalance is linked to many disorders, such as inflammation and oxidative stress, thereby contributing to cardiovascular disease, obesity, diabetes and chronic kidney disease (CKD) complications. Novel therapeutic strategies that aim to reduce the complications caused by this imbalance have increased in recent years. Studies have shown that prebiotic supplementation can beneficially modulate the gut microbiota in CKD patients. Prebiotics consist of non-digestible dietary soluble fiber, which acts as a substrate for the gut microbiota. Resistant starch (RS) is a type of dietary fiber that can reach the large bowel and act as a substrate for microbial fermentation; for these reasons, it has been considered to be a prebiotic. Few studies have analyzed the effects of RS on the gut microbiota in CKD patients. This review discusses recent information about RS and the potential role of the gut microbiota, with a particular emphasis on CKD patients.

Protein-Bound Uremic Toxins from Gut Microbiota and Inflammatory Markers in Chronic Kidney Disease.

OBJECTIVE: Protein-bound uremic toxins from gut microbiota tend to accumulate in chronic kidney disease (CKD) patients and are poorly removed by current dialysis techniques. These toxins induce inflammation and are associated with cardiovascular disease (CVD). The aim of this study was to report the relationship between uremic toxins and inflammatory and cardiovascular markers in CKD patients. DESIGN: This was a cross sectional study. SUBJECTS: Twenty-one nondialysis patients were included (43% men, 63.0 ± 7.8 years, glomerular filtration rate: 34.4 ± 12.5 mL/min) as well as 29 hemodialysis (HD) patients [58% men, 52.7 ± 10.3 years, time on dialysis 54 (31-94.5 months)]. MAIN OUTCOME MEASURE: Total levels of uremic toxins (IS, p-CS, and IAA) were assessed by high-performance liquid chromatography with fluorescence detection. C-reactive protein, Interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and calprotectin plasma levels were determined by immunometric assays. RESULTS: HD patients presented higher inflammatory markers and uremic toxins levels than nondialysis patients. IL-6 levels were positively correlated with IS (r = 0.49; P = .03), p-CS (r = 0.35; P = .04) and IAA (r = 0.36; P = .03). A positive correlation was also observed between MCP-1 levels with IS (r = 0.72; P = .001), p-CS (r = 0.48; P = .001) and IAA (r = 0.75; P = .0001). Linear regression showed that IS was an independent predictor for IL-6 and MCP-1 levels after adjustment. CONCLUSION: Plasma uremic toxins were associated with higher IL-6 and MCP-1 levels in CKD patients, potentially playing a role in the development of CVD.

Effects of acute resistance exercise on acyl-ghrelin and obestatin levels in hemodialysis patients: a pilot study.

Chronic physical exercises may be beneficial to modulate appetite hormones as acyl-ghrelin (orexigenic) and obestatin (anorexigenic) in chronic kidney disease (CKD) patients; however, there are no data about the effects of acute exercises on these hormones. Thus, the aim of the present study was to assess the effect of acute resistance exercise on appetite hormones (acyl-ghrelin and obestatin) of patients undergoing hemodialysis (HD). Twenty-five patients (44.7 ± 12.9 years, 68% women) on regular HD program were enrolled into two groups, 16 patients performed exercises and 9 patients comprised the control group. The patients performed the exercises in both lower limbs with ankle-cuffs and elastic bands, 30 min after the initiation of hemodialysis session. Blood samples of both the groups were drawn in the morning before and after 30 min with exercise session (exercise group) and, before and after the same time without exercise (control group). Acyl-ghrelin and obestatin plasma levels were measured using an enzyme immunometric assay. Acyl-ghrelin plasma levels did not change in both the groups. However, when stratified by gender the acyl-ghrelin increased significantly right after exercise in men [32.1 pg/mL (25.6-41.2) to 46.0 pg/mL (39.0-59.5)] (p = 0.04). Obestatin plasma levels reduced after a single bout of exercise and changes remained significantly when the sample was stratified by gender. There was no change in obestatin plasma levels in control group. A single bout of resistance exercise seems to modulate the levels of appetite hormones in HD patients.

What Can the Gut Microbiota of Animals Teach Us about the Relationship between Nutrition and Burden of Lifestyle Diseases?

The gut microbiota performs several crucial roles in a holobiont with its host, including immune regulation, nutrient absorption, synthesis, and defense against external pathogens, significantly influencing host physiology. Disruption of the gut microbiota has been linked to various chronic conditions, including cardiovascular, kidney, liver, respiratory, and intestinal diseases. Studying how animals adapt their gut microbiota across their life course at different life stages and under the dynamics of extreme environmental conditions can provide valuable insights from the natural world into how the microbiota modulates host biology, with a view to translating these into treatments or preventative measures for human diseases. By modulating the gut microbiota, opportunities to address many complications associated with chronic diseases appear. Such a biomimetic approach holds promise for exploring new strategies in healthcare and disease management.

Gut Microbiota Interventions to Retain Residual Kidney Function.

Residual kidney function for patients with chronic kidney disease (CKD) is associated with better quality of life and outcome; thus, strategies should be implemented to preserve kidney function. Among the multiple causes that promote kidney damage, gut dysbiosis due to increased uremic toxin production and endotoxemia need attention. Several strategies have been proposed to modulate the gut microbiota in these patients, and diet has gained increasing attention in recent years since it is the primary driver of gut dysbiosis. In addition, medications and faecal transplantation may be valid strategies. Modifying gut microbiota composition may mitigate chronic kidney damage and preserve residual kidney function. Although various studies have shown the influential role of diet in modulating gut microbiota composition, the effects of this modulation on residual kidney function remain limited. This review discusses the role of gut microbiota metabolism on residual kidney function and vice versa and how we could preserve the residual kidney function by modulating the gut microbiota balance.

Consumption of Fish in Chronic Kidney Disease - A Matter of Depth.

Fish is an excellent source of ω-3 polyunsaturated fatty acids (PUFAs), amino acids, collagen, vitamins, and iodine and its intake is associated with health benefits, mainly reduces risk of cardiovascular mortality. However, recent studies have shown that fish is also an important source of trimethylamine N-oxide (TMAO), a uremic toxin produced by the gut microbiota that promotes an increased risk of cardiovascular diseases. In patients with chronic kidney disease (CKD), TMAO levels are markedly increased due to gut dysbiosis and reduced kidney function. No study has yet evaluated the effects of a fish-rich diet on TMAO plasma levels and cardiovascular outcomes. This review discusses the pros and cons of a fish-rich diet in patients with CKD - a matter of depth.

Oral iron supplementation in patients with chronic kidney disease: Can it be harmful to the gut microbiota?

Patients with chronic kidney disease (CKD) have several pathophysiological alterations, including anemia, one of the first changes in CKD patients. More recently, researchers have observed that the intestinal microbiota alterations are also another complication in these patients. The most common treatment for anemia is oral (mainly ferrous sulfate) or intravenous iron supplementation. Despite being a necessary treatment, recent studies have reported that supplementation with oral iron may increase its availability in the intestine, leading to disturbance in the gut microbiota and also to oxidative stress in the enterocytes, which may change the permeability and the microbiota profile. Although it is a therapy routinely used in patients with CKD, supplementation with oral iron on the gut microbiota has been rarely studied in these patients. Thus, this review will discuss the relationship between iron and the gut microbiota and the possible effects of oral iron supplementation on gut microbiota in patients with CKD.

Pink pressure: beetroot (Beta vulgaris rubra) as a possible novel medical therapy for chronic kidney disease.

Chronic kidney disease (CKD) manifests with systemic inflammation, oxidative stress, and gut dysbiosis, resulting in metabolic disorders and elevated rates of cardiovascular disease-associated death. These all correlate with a high economic cost to healthcare systems. Growing evidence indicates that diet is an indispensable ally in the prevention and management of CKD and its complications. In this context, the root vegetable beetroot (Beta vulgaris rubra) deserves special attention because it is a source of several bioactive compounds, such as nitrate, betaine, and betalain, and has shown beneficial effects in CKD, including reduction of blood pressure, anti-inflammatory effects, and antioxidant actions by scavenging radical oxidative species, as observed in preclinical studies. Beetroot consumption as a possible therapeutic strategy to improve the clinical treatment of patients with CKD and future directions for clinical studies are addressed in this narrative review.

Bicycle ergometer exercise during hemodialysis and its impact on quality of life, aerobic fitness and dialysis adequacy: A pilot study.

BACKGROUND: Chronic kidney disease patients on hemodialysis commonly have a worse quality of life (QoL) due to complications of the disease and dialysis procedure. Physical exercise has emerged as a strategy to improve this scenario. The objective of this study was to evaluate the effect of an intradialytic aerobic exercise program on QoL and aerobic fitness in hemodialysis patients. MATERIAL AND METHODS: These are a secondary analysis of clinical trial data previously published in which hemodialysis patients were randomized into "bike group" (using an adapted exercise bicycle) or "control group" (usual care). The exercise sessions lasted 45 min (5 min of warm-up, 35 min of moderate-intensity and 5 min of cool-down) three times/week for three months. The QoL domains were assessed using the SF-36 QoL questionnaire. Aerobic fitness was evaluated using the 6-min walk test (6MWT). Circulating cytokines, biochemical parameters and Kt/V were also assessed. RESULTS: Nine patients completed three months of exercise (5 men, 44 ± 11 years), and nine were in the control group (6 men, 44 ± 14 years). In the bike group, there was a trend to improve the physical role domain (p = 0.06) regarding QoL, an improvement in the 6MWT (p = 0.02), and in the Kt/V (p = 0.03) after three months. There was a positive correlation between the general health domain and Kt/V (r = 0.691; p = 0.003) and an inverse correlation between the physical functioning domain and plasma TNF-α levels (r = -0.514; p = 0.04). CONCLUSIONS: 12 weeks of intradialytic aerobic exercise was enough to benefit hemodialysis patients' quality of life, aerobic fitness, and quality of dialysis. CLINICALTRIALS: gov id: NCT04375553.

Food as medicine: targeting the uraemic phenotype in chronic kidney disease.

The observation that unhealthy diets (those that are low in whole grains, fruits and vegetables, and high in sugar, salt, saturated fat and ultra-processed foods) are a major risk factor for poor health outcomes has boosted interest in the concept of 'food as medicine'. This concept is especially relevant to metabolic diseases, such as chronic kidney disease (CKD), in which dietary approaches are already used to ameliorate metabolic and nutritional complications. Increased awareness that toxic uraemic metabolites originate not only from intermediary metabolism but also from gut microbial metabolism, which is directly influenced by diet, has fuelled interest in the potential of 'food as medicine' approaches in CKD beyond the current strategies of protein, sodium and phosphate restriction. Bioactive nutrients can alter the composition and metabolism of the microbiota, act as modulators of transcription factors involved in inflammation and oxidative stress, mitigate mitochondrial dysfunction, act as senolytics and impact the epigenome by altering one-carbon metabolism. As gut dysbiosis, inflammation, oxidative stress, mitochondrial dysfunction, premature ageing and epigenetic changes are common features of CKD, these findings suggest that tailored, healthy diets that include bioactive nutrients as part of the foodome could potentially be used to prevent and treat CKD and its complications.

To bee or not to bee? The bee extract propolis as a bioactive compound in the burden of lifestyle diseases.

Propolis is a polyphenolic plant resin collected by bees to protect hives against pathogens and temperature drop. It exhibits antibacterial, antioxidant, and antiinflammatory properties. Propolis has been reported to possess antidiabetic properties and display beneficial effects against cardiovascular disease, gut dysbiosis, and chronic kidney disease. It has an excellent clinical safety profile, with no known toxic effects described so far. In this review, we discuss the salutogenic effects of propolis, with particular reference to modulating notable features of chronic kidney disease, notably those involving cardiovascular risks.

Can nutritional interventions modulate the activation of the NLRP3 inflammasome in chronic kidney disease?

Inflammatory and innate immune responses triggered by pathogen-associated and other danger-associated signals emerging during infections, results in the activation of cytosolic inflammasomes. The nod-like receptor pyrin domain containing 3 (NLRP3) is one of the inflammasomes mediating such responses through the activation of caspase-1, which increases the production and release of pro-inflammatory cytokines, such as IL-1ß and IL-18 and induces programmed cell death through pyroptosis. NLRP3 is thought to play a crucial role in the underlying inflammatory responses in many lifestyles related chronic diseases. Consequently, research on the NLRP3 inflammasome has expanded dramatically in recent years. Although several studies have investigated the role of NLRP3 activation in chronic kidney disease (CKD), few studies have evaluated strategies to modulate its activation by means of interventions using non-pharmacological strategies. This review discusses some nutritional strategies (bioactive compounds, probiotics and caloric restriction) that have been shown to influence NLRP3 in experimental models of renal disease, and in CKD. It discusses how nutritional interventions could potentially dampen NLRP3 associated inflammatory burden, as part of nutritional strategies to prevent and treat CKD and its complications.

Dietary intake of tyrosine and phenylalanine, and p-cresyl sulfate plasma levels in non-dialyzed patients with chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) present an imbalance of the gut microbiota composition, leading to increased production of uremic toxins like p-cresyl sulfate (PCS), product from bacterial fermentation of the amino acids tyrosine (Tyr) and phenylalanine (Phe) from the diet. Thus, diet may be a determinant in the uremic toxins levels produced by the gut microbiota. The aim of this study was to evaluate the possible relationship between Tyr and Phe intake and PCS plasma levels in non-dialysis CKD patients. METHODS: Twenty-seven non-dialysis CKD patients (stages 3 and 4) without previous nutritional intervention were evaluated. The dietary intake was evaluated using a 24-hour recall, 3-day food record and protein intake was also estimated by Protein Nitrogen Appearance (PNA). The plasma levels of PCS were measured using reverse phase high performance liquid chromatography. RESULTS: The evaluated patients (GRF, 34.8 ± 12.4 mL/min, 54.2 ± 14.3 years, BMI, 29.3 ± 6.1 kg/m2) presented mean protein intake of 1.1 ± 0.5 g/kg/day), Tyr of 4.5 ± 2.4 g/day and Phe of 4.6 ± 2.5 g/day. PCS plasma levels (20.4 ± 15.5 mg/L) were elevated and positively associated with both, Tyr (r = 0.58, p = 0.002) and Phe intake (r = 0.53, p = 0.005), even after adjustments for eGFR and age. CONCLUSION: This study suggests that the diet is an important modulator of the uremic toxins plasma levels produced by the gut microbiota, in non-dialysis CKD patients.

Effects of Probiotic Supplementation on Trimethylamine-N-Oxide Plasma Levels in Hemodialysis Patients: a Pilot Study.

Components present in the diet, L-carnitine, choline, and betaine are metabolized by gut microbiota to produce metabolites such as trimethylamine-N-oxide (TMAO) that appear to promote cardiovascular disease in chronic kidney disease (CKD) patients. The objective of this pilot study was to evaluate the effects of probiotic supplementation for 3 months on plasma TMAO levels in CKD patients on hemodialysis (HD). A randomized, double-blind trial was performed in 21 patients [54.8 ± 10.4 years, nine men, BMI 26.1 ± 4.8 kg/m2, dialysis vintage 68.5 (34.2-120.7) months]. Ten patients were randomly allocated to the placebo group and 11 to the probiotic group [three capsules, totaling 9 × 1013 colony-forming units per day of Streptococcus thermophilus (KB19), Lactobacillus acidophilus (KB27), and Bifidobacteria longum (KB31). Plasma TMAO, choline, and betaine levels were measured by LC-MS/MS at baseline and after 3 months. While TMAO did not change after probiotic supplementation, there was a significant increase in betaine plasma levels. In contrast, the placebo group showed a significant decrease in plasma choline levels. Short-term probiotic supplementation does not appear to influence plasma TMAO levels in HD patients. Long-term studies are needed to determine whether probiotics may affect TMAO production in CKD patients.

From bench to the hemodialysis clinic: protein-bound uremic toxins modulate NF-κB/Nrf2 expression.

PURPOSE: Uremic toxins produced by gut microbiota (indoxyl sulfate-IS, p-cresyl sulfate-p-CS, and indole-3-acetic acid-IAA) accumulate in hemodialysis (HD) patients and exhibit potent inflammatory effects. However, the impact of these toxins on nuclear E2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) expression in HD patients remains poorly defined. The aim of this study was to evaluate the association between uremic toxins and Nrf2/NF-κB expression in vitro (RAW 264.7 macrophage-like cells) and in peripheral blood mononuclear cells from HD patients. METHODS: Uremic toxins, C-reactive protein (CRP), interleukin-6 (IL-6) and malondialdehyde (MDA) levels were measured in fifteen HD patients and nine healthy individuals. RAW 264.7 macrophage-like cells were incubated with IS, as a prototype of protein-bound uremic toxin. Nrf2 and NF-κB expressions were analyzed by RT-qPCR. RESULTS: HD patients presented high levels of inflammatory markers, MDA and uremic toxins. In addition, they presented high NF-κB and low Nrf2 expression. Uremic toxins were positively correlated with NF-κB expression (IS, ρ = 0.58, p < 0.003; p-CS, ρ = 0.71, p < 0.001; IAA, ρ = 0.62, p < 0.001) and negatively with Nrf2 (IS, ρ = - 0.48, p = 0.01; p-CS, ρ = - 0.46, p < 0.02). Uremic toxins also exhibited positive correlations with CRP and MDA levels. Multivariate analysis revealed that p-CS is a determinant factor of NF-κB expression. In RAW 264.7 culture, NF-κB mRNA expression was stimulated by IS, while Nrf2 was downregulated. CONCLUSIONS: Thus, uremic toxins may stimulate NF-κB mRNA and decrease Nrf2 expression in HD patients and, consequently, trigger inflammation and oxidative stress.