Chronic kidney disease and the gut microbiome.

The gut microbiome is composed of a diverse population of bacteria that have beneficial and adverse effects on human health. The microbiome has recently gained attention and is increasingly noted to play a significant role in health and a number of disease states. Increasing urea concentration during chronic kidney disease (CKD) leads to alterations in the intestinal flora that can increase production of gut-derived toxins and alter the intestinal epithelial barrier. These changes can lead to an acceleration of the process of kidney injury. A number of strategies have been proposed to interrupt this pathway of injury in CKD. The purpose of this review is to summarize the role of the gut microbiome in CKD, tools used to study this microbial population, and attempts to alter its composition for therapeutic purposes.

Effect of prebiotic (fructooligosaccharide) on uremic toxins of chronic kidney disease patients: a randomized controlled trial.

BACKGROUND: Microbial-derived uremic toxins, p-cresyl sulfate (PCS), indoxyl sulfate (IS) and indole 3-acetic acid (IAA), have been associated with the burden of chronic kidney disease (CKD). Prebiotics have emerged as an alternative to modulate the gut environment and to attenuate toxin production. This trial aims to investigate the effect of a prebiotic fructooligosaccharide (FOS) on uremic toxins of non-dialysis-dependent CKD (NDD-CKD) patients. METHODS: A double-blind, placebo-controlled, randomized trial was conducted for 3 months. In all, 50 nondiabetic NDD-CKD patients [estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2], aged 18-80 years, were allocated to prebiotic (FOS, 12 g/day) or placebo (maltodextrin, 12 g/day) groups. Primary outcomes were changes in serum (total and free) and urinary (total) PCS. Secondary outcomes included changes in IS, IAA, serum markers of intestinal permeability (zonulin), gut-trophic factors (epidermal growth factor and glucagon-like peptide-2), eGFR, inflammation (high sensitive c-reactive protein and interleukin-6), homeostatic model assessment-insulin resistance, lipid profile and gastrointestinal symptoms. RESULTS: From 50 participants (54% men, 57.3 ± 14.6 years and eGFR 21.4 ± 7.6 mL/min/1.73 m2), 46 completed the follow-up. No changes in dietary intake or gastrointestinal symptoms were observed. There was a trend in the difference of serum total ΔPCS (treatment effect adjusted for baseline levels: -12.4 mg/L; 95% confidence interval (-5.6 to 0.9 mg/L; P = 0.07) and serum-free Δ%PCS [intervention -8.6 (-41.5 to 13.9%) versus placebo 3.5 (-28.8 to 85.5%); P = 0.07] between the groups. The trend in the difference of serum total ΔPCS was independent of eGFR and dietary protein:fiber ratio intake. No difference was found in urinary PCS. Aside from the decreased high-density lipoprotein cholesterol in the intervention, no differences were observed in the change of IS, IAA or other secondary outcome between the groups. CONCLUSIONS: Our result suggests the potential of FOS in reducing serum total and free PCS in nondiabetic NDD-CKD patients.

Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats.

BACKGROUND: Constipation is frequently observed in patients with chronic kidney disease (CKD). Lactulose is expected to improve the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic. We studied the effect of lactulose on renal function in adenine-induced CKD rats and monitored uremic toxins and gut microbiota. METHODS: Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce CKD. Then, they were divided into three groups and fed as follows: control, normal diet; and 3.0- and 7.5-Lac, 3.0% and 7.5% lactulose-containing diets, respectively, for 4 weeks. Normal diet group was fed normal diet for 7 weeks. The rats were observed for parameters including renal function, uremic toxins, and gut microbiota. RESULTS: The control group showed significantly higher serum creatinine (sCr) and blood urea nitrogen (BUN) 3 weeks after adenine feeding than at baseline, with a 8.5-fold increase in serum indoxyl sulfate (IS). After switching to 4 weeks of normal diet following adenine feeding, the sCr and BUN in control group remained high with a further increase in serum IS. In addition, tubulointerstitial fibrosis area was increased in control group. On the other hand, 3.0- and 7.5-Lac groups improved sCr and BUN levels, and suppressed tubulointerstitial fibrosis, suggesting preventing of CKD progression by lactulose. Lac groups also lowered level of serum IS and proportions of gut microbiota producing IS precursor. CONCLUSION: Lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxin production.

Chronic kidney disease, uremic milieu, and its effects on gut bacterial microbiota dysbiosis.

Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57BL/6J mice that underwent a remnant kidney model and establish that changes in microbiota take place in the early gastrointestinal tract. Increased intestinal urea concentration has been hypothesized as a leading contributor to dysbiotic changes in CKD. We show that urea transporters (UT)-A and UT-B mRNA are both expressed throughout the whole gastrointestinal tract. The noted increase in intestinal urea concentration appears to be independent of UTs' expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD- associated dysbiosis.

Evaluating the anti-biofilm and antibacterial effects of Juglans regia L. extracts against clinical isolates of Pseudomonas aeruginosa.

OBJECTIVE: Pseudomonas aeruginosa, an opportunistic pathogen, can cause serious health problems and produces several virulence factors. The most important of these factors is biofilm. Many studies suggest administration of new generation of antibiotics, as P. aeruginosa biofilm has developed high resistance to antimicrobial drugs. Emergence of multidrug resistant (MDR) strains has resulted in screening biofilm inhibitors from natural products or modified from natural compounds. To test this hypothesis, we evaluated the inhibitory effects (antibacterial and antibiofilm) of Juglans regia L. extract on biofilm formation by clinical isolates of P. aeruginosa. METHODS: Samples collected from burn, tracheal and urine infections of hospitalized patients (Shahid Motahari Hospital, Tehran, Iran) were identified as P. aeruginosa using traditional biochemical tests. Antibiotic susceptibility testing of isolates was performed using disk diffusion method. The microtiter plate method was used to evaluate the ability of pathogenic strains in producing biofilm. Antibacterial and antibiofilm effects of aqueous and methanol Juglans regia L. leaf extracts were determined by microtiter plate method. RESULTS: 46.7% of P. aeruginosa isolates (n = 50) were resistant to gentamicin and 100% of them could form a biofilm. All isolates (100%) exhibited MDR phenotype. Various concentrations of Juglans regia L. extracts exhibited significant effects on the growth and biofilm inhibition of the isolates. In addition, aqueous Juglans regia L. leaf extract had better inhibition activity on planktonic growth, and methanol extract was more effective on inhibiting biofilm of P. aeruginosa. CONCLUSIONS: The results of this study indicate that antibiotic-resistant strains were significantly associated with biofilm formation. The J. regia L. extract, at various concentrations, may provide an alternative to control biofilm-related infections caused by P. aeruginosa. Further analyses are needed to validate the antibiofilm activity of these medicinal plants.

Microbiota metabolites: Pivotal players of cardiovascular damage in chronic kidney disease.

In chronic kidney disease (CKD), cardiovascular (CV) damage is present in parallel which leads to an increased risk of CV disease. Both traditional and non-traditional risk factors contribute to CV damage in CKD. The systemic role of the microbiota as a central player in the pathophysiology of many organs is progressively emerging in the literature: the microbiota is indeed involved in a complex, bi-directional network between many organs, including the kidney and heart connection, although many of these relationships still need to be elucidated through in-depth mechanistic studies. The aim of this review is to provide evidence that microbiota metabolites influence non-traditional risk factors, such as inflammation and endothelial dysfunction in CKD-associated CV damage. Here, we report our current understanding and hypotheses on the gut-kidney and gut-heart axes and provide details on the potential mechanisms mediated by microbial metabolites. More specifically, we summarize some novel hypotheses linking the microbiota to blood pressure regulation and hypertension. We also emphasise the idea that the nutritional management of CKD should be redesigned and include the new findings from research on the intrinsic plasticity of the microbiota and its metabolites in response to food intake. The need is felt to integrate the classical salt and protein restriction approach for CKD patients with foods that enhance intestinal wellness. Finally, we discuss the new perspectives, especially the importance of taking care of the microbiota in order to prevent the risk of developing CKD and hypertension, as well as the still not tested but very promising CKD innovative treatments, such as postbiotic supplementation and bacteriotherapy. This interesting area of research offers potential complementary approaches to the management of CKD and CV damage assuming that the causal mechanisms underlying the gut-kidney and gut-heart axes are clarified. This will pave the way to the design of new personalized therapies targeting gut microbiota.

Manipulating the gut microbiome to decrease uremic toxins.

The uremic solute indoxyl sulfate has been associated with increased mortality and other adverse outcomes in patients with chronic kidney disease. In a recent study published in Cell Host & Microbe, Devlin et al. describe a novel approach to alter the production of indoxyl sulfate through manipulation of the gut microbiota. Although this approach is far from clinical application, it may allow investigators to determine the contribution of uremic solutes to disease pathogenesis.

The gut-kidney axis.

The host-gut microbiota interaction has been the focus of increasing interest in recent years. It has been determined that this complex interaction is not only essential to many aspects of normal "mammalian" physiology but that it may also contribute to a multitude of ailments, from the obvious case of inflammatory bowel disease to (complex) diseases residing in organs outside the gut. An increasing body of evidence indicates that crosstalk between host and microbiota is pathophysiologically relevant in patients with chronic kidney disease (CKD). Interactions are bidirectional; on the one hand, uremia affects both the composition and metabolism of the gut microbiota and, on the other hand, important uremic toxins originate from microbial metabolism. In addition, gut dysbiosis may induce a disruption of the epithelial barrier, ultimately resulting in increased exposure of the host to endotoxins. Due to dietary restrictions and gastrointestinal dysfunctions, microbial metabolism shifts to a predominantly proteolytic fermentation pattern in CKD. Indoxyl sulfate and p-cresyl sulfate, both end-products of protein fermentation, and trimethylamine-N-oxide, an end-product of microbial choline and carnitine metabolism, are prototypes of uremic toxins originating from microbial metabolism. The vascular and renal toxicity of these co-metabolites has been demonstrated extensively in experimental and clinical studies. These co-metabolites are an appealing target for adjuvant therapy in CKD. Treatment options include dietary therapy, prebiotics, probiotics and host and bacterial enzyme inhibitors. Final proof of the concept should come from randomized controlled and adequately powered intervention studies.

The role of the gastrointestinal tract and microbiota on uremic toxins and chronic kidney disease development.

It is well-established that uremic toxins are positively correlated with the risk of developing chronic kidney disease and cardiovascular disease. In addition, emerging data suggest that gut bacteria exert an influence over both the production of uremic toxins and the development of chronic kidney disease. As such, modifying the gut microbiota may have the potential as a treatment for chronic kidney disease. This is supported by data that suggest that rescuing microbiota dysbiosis may: reduce uremic toxin production; prevent toxins and pathogens from crossing the intestinal barrier; and, reduce gastrointestinal tract transit time allowing nutrients to reach the microbiota in the distal portion of the gastrointestinal tract. Despite emerging literature, the gut-kidney axis has yet to be fully explored. A special focus should be placed on examining clinically translatable strategies that might encourage improvements to the microbiome, thereby potentially reducing the risk of the development of chronic kidney disease. This review aims to present an overview of literature linking changes to the gastrointestinal tract with microbiota dysbiosis and the development and progression of chronic kidney disease.

The Leaky Gut and Altered Microbiome in Chronic Kidney Disease.

Chronic kidney disease results in disruption of the intestinal epithelial barrier as well as profound changes in the gut microbial flora. These events are largely mediated by (1) heavy influx of circulating urea to the gut lumen and (2) dietary restrictions of foods containing high fiber (such as fruits and vegetable) and symbiotic organisms (such as yogurt and cheese) imposed to mitigate hyperkalemia and hyperphosphatemia. Collectively, these factors promote systemic inflammation and cardiovascular morbidity by mediating microbial dysbiosis, disruption of the intestinal epithelial barrier, and translocation of endotoxin, bacterial fragments, and uremic toxins across the "leaky gut" into the bloodstream. Strategies aimed at increasing dietary fiber and lowering urea burden may help to attenuate uremia-induced microbial dysbiosis and epithelial barrier breakdown, and thereby improve systemic inflammation.

Chronic kidney disease alters intestinal microbial flora.

The population of microbes (microbiome) in the intestine is a symbiotic ecosystem conferring trophic and protective functions. Since the biochemical environment shapes the structure and function of the microbiome, we tested whether uremia and/or dietary and pharmacologic interventions in chronic kidney disease alters the microbiome. To identify different microbial populations, microbial DNA was isolated from the stools of 24 patients with end-stage renal disease (ESRD) and 12 healthy persons, and analyzed by phylogenetic microarray. There were marked differences in the abundance of 190 bacterial operational taxonomic units (OTUs) between the ESRD and control groups. OTUs from Brachybacterium, Catenibacterium, Enterobacteriaceae, Halomonadaceae, Moraxellaceae, Nesterenkonia, Polyangiaceae, Pseudomonadaceae, and Thiothrix families were markedly increased in patients with ESRD. To isolate the effect of uremia from inter-individual variations, comorbid conditions, and dietary and medicinal interventions, rats were studied 8 weeks post 5/6 nephrectomy or sham operation. This showed a significant difference in the abundance of 175 bacterial OTUs between the uremic and control animals, most notably as decreases in the Lactobacillaceae and Prevotellaceae families. Thus, uremia profoundly alters the composition of the gut microbiome. The biological impact of this phenomenon is unknown and awaits further investigation.

The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease.

Chronic kidney disease (CKD) and end-stage renal disease (ESRD) are associated with systemic inflammation and acquired immunodeficiency, which promote cardiovascular disease, body wasting, and infections as leading causes of death. This phenomenon persists despite dialysis-related triggers of immune deregulation having been largely eliminated. Here we propose a potential immunoregulatory role of the intestinal microbiota in CKD/ESRD. We discuss how the metabolic alterations of uremia favor pathogen overgrowth (dysbiosis) in the gut and an increased translocation of living bacteria and bacterial components. This process has the potential to activate innate immunity and systemic inflammation. Persistent innate immune activation involves the induction of immunoregulatory mediators that suppress innate and adaptive immunity, similar to the concept of 'endotoxin tolerance' or 'immune paralysis' in advanced sepsis or chronic infections. Renal science has largely neglected the gut as a source of triggers for CKD/ESRD-related immune derangements and complications and lags behind on the evolving microbiota research. Interdisciplinary research activities at all levels are needed to unravel the pathogenic role of the intestinal microbiota in kidney disease and to evaluate if therapeutic interventions that manipulate the microbiota, such as pre- or probiotics, have a therapeutic potential to correct CKD/ESRD-related immune deregulation and to prevent the associated complications.

Increase in extraintestinal infections caused by Salmonella enterica subspecies II-IV.

To garner information regarding site of infection and age and sex of persons infected with Salmonella enterica subspecies II-IV, we retrospectively analyzed data on Salmonella spp. infections in California, USA, 1985-2009. These subspecies were found to cause significantly more frequent invasive disease (e.g., bacteremia) than did Salmonella subspecies I strains.

Uremic solutes from colon microbes.

There is renewed interest in identifying organic waste solutes that are normally excreted by the kidneys and must be removed by renal replacement therapy when the kidneys fail. A large number of these waste solutes are produced by colon microbes. Mass spectrometry is expanding our knowledge of their chemical identity, and DNA sequencing technologies are providing new knowledge of the microbes and metabolic pathways by which they are made. There is evidence that the most extensively studied of the colon-derived solutes, indoxyl sulfate and p-cresol sulfate, are toxic. Much more study is required to establish the toxicity of other solutes in this class. Because they are made in an isolated compartment by microbes, their production may prove simpler to suppress than the production of other waste solutes. To the extent that they are toxic, suppressing their production could improve the health of renal failure patients without the need for more intensive or prolonged dialysis.

CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is associated with oxidative stress and inflammation which contribute to progression of kidney disease and its numerous complications. Until recently, little attention had been paid to the role of the intestine and its microbial flora in the pathogenesis of CKD-associated inflammation. This article is intended to provide an over view of the impact of uremia on the structure and function of the gut and its microbial flora and their potential link to the associated systemic inflammation. RECENT FINDINGS: Recent studies conducted in the author's laboratories have demonstrated marked disintegration of the colonic epithelial barrier structure and significant alteration of the colonic bacterial flora in humans and animals with advanced CKD. The observed disruption of the intestinal epithelial barrier complex can play an important part in the development of systemic inflammation by enabling influx of endotoxin and other noxious luminal contents into the systemic circulation. Similarly via disruption of the normal symbiotic relationship and production, absorption and retention of noxious products, alteration of the microbial flora can contribute to systemic inflammation and uremic toxicity. In fact recent studies have documented the role of colonic bacteria as the primary source of several well known pro-inflammatory/pro-oxidant uremic toxins as well as many as-yet unidentified retained compounds. SUMMARY: CKD results in disruption of the intestinal barrier structure and marked alteration of its microbial flora - events that play a major role in the pathogenesis of inflammation and uremic toxicity.

Gut bacterial translocation contributes to microinflammation in experimental uremia.

BACKGROUND: Microinflammation frequently develops in chronic uremia with pathological intestinal changes. However, the relationship between gut bacterial translocation and microinflammation in uremia has not been widely investigated. AIM: This study aimed to investigate whether gut microbiome dysbiosis and translocation occurred in experimental uremia, and whether they consequently contributed to microinflammation. METHODS: Forty rats underwent surgical renal mass 5/6 ablation. The surviving (uremic group, n = 21) and healthy (sham group, n = 20) rats were used in the experiment. Postoperative blood, livers, spleens, and mesenteric lymph nodes (MLNs) were subjected to bacterial 16S ribosomal DNA amplification to determine if bacteria were present. Bacterial genomic DNA samples from the MLNs and colon were amplified with specific primers designed by the 16S rRNA sequence of the species obtained from blood, livers, and spleens. Pyrosequencing was used to analyze the colonic microbiome of each subject. Intestinal permeability to (99m)Tc-DTPA, plasma hs-CRP, and IL-6 were measured. RESULTS: Bacterial DNA in extraintestinal sites and altered colonic microbiomes were detected in some rats in the uremic group. Bacterial genomic DNA in MLNs and colon were obtained by primers specific for bacterial species observed from blood, livers, and spleens of identical individuals. Intestinal permeability, plasma hs-CRP, and IL-6 levels were statistically higher in the uremic group compared with the sham group. Plasma hs-CRP and IL-6 were significantly higher in uremic rats with bacterial DNA in their blood than in those without. CONCLUSIONS: Gut microbiome dysbiosis occurs and bacteria translocate to the systemic and lymph circulation, thereby contributing to microinflammation in experimental uremia.

Contribution of Uremia to Ureaplasma-Induced Hyperammonemia.

Lung transplant recipients (LTRs) are vulnerable to hyperammonemia syndrome (HS) in the early postoperative period, a condition typically unresponsive to nonantibiotic interventions. HS in LTRs is strongly correlated with Ureaplasma infection of the respiratory tract, although it is not well understood what makes LTRs preferentially susceptible to HS compared to other immunocompromised hosts. Ureaplasma species harbor highly active ureases, and postoperative LTRs commonly experience uremia. We hypothesized that uremia could be a potentiating comorbidity, providing increased substrate for ureaplasmal ureases. Using a novel dialyzed flow system, the ammonia-producing capacities of four isolates of Ureaplasma parvum and six isolates of Ureaplasma urealyticum in media formulations relating to normal and uremic host conditions were tested. For all isolates, growth under simulated uremic conditions resulted in increased ammonia production over 24 h, despite similar endpoint bacterial quantities. Further, transcripts of ureC (from the ureaplasmal urease gene cluster) from U. urealyticum IDRL-10763 and ATCC-27816 rose at similar rates under uremic and nonuremic conditions, with similar endpoint populations under the two conditions (despite markedly increased ammonia concentrations under uremic conditions), indicating that the difference in ammonia production by these isolates is due to increased urease activity, not expression. Lastly, uremic mice infected with an Escherichia coli strain harboring a U. urealyticum serovar 8 gene cluster exhibited higher blood ammonia levels compared to nonuremic mice infected with the same strain. Taken together, these data show that U. urealyticum and U. parvum produce more ammonia under uremic conditions compared to nonuremic conditions. This implies that uremia is a plausible contributing factor to Ureaplasma-induced HS in LTRs. IMPORTANCE Ureaplasma-induced hyperammonemia syndrome is a deadly complication affecting around 4% of lung transplant recipients and, to a lesser extent, other solid organ transplant patients. Understanding the underlying mechanisms will inform patient management, potentially decreasing mortality and morbidity. Here, it is shown that uremia is a plausible contributing factor to the pathophysiology of the condition.

Dysbiosis in Patients with Chronic Kidney Disease: Let Us Talk About Vitamin K.

PURPOSE OF REVIEW: This narrative review aimed to summarize the current evidence on the connection between dysbiosis and vitamin K deficiency in patients with chronic kidney disease (CKD). The presence of dysbiosis (perturbations in the composition of the microbiota) has been described in several non-communicable diseases, including chronic kidney disease, and it has been hypothesized that dysbiosis may cause vitamin K deficiency. Patients with CKD present both vitamin K deficiency and gut dysbiosis; however, the relationship between gut dysbiosis and vitamin K deficiency remains to be addressed. RECENT FINDINGS: Recently, few studies in animals have demonstrated that a dysbiotic environment is associated with low production of vitamin K by the gut microbiota. Vitamin K plays a vital role in blood coagulation as well as in the cardiovascular and bone systems. It serves as a cofactor for γ-glutamyl carboxylases and thus is essential for the post-translational modification and activation of vitamin K-dependent calcification regulators, such as osteocalcin, matrix Gla protein, Gla-rich protein, and proteins C and S. Additionally, vitamin K executes essential antioxidant and anti-inflammatory functions. Dietary intake is the main source of vitamin K; however, it also can be produced by gut microbiota. This review discusses the effects of uremia on the imbalance in gut microbiota, vitamin K-producing bacteria, and vitamin K deficiency in CKD patients, leading to a better understanding and raising hypothesis for future clinical studies.

Uremia Coupled with Mucosal Damage Predisposes Mice with Kidney Disease to Systemic Infection by Commensal Candida albicans.

Infections are the second major cause of mortality in patients with kidney disease and accompanying uremia. Both vascular access and non-access-related infections contribute equally to the infection-related deaths in patients with kidney disease. Dialysis is the most common cause of systemic infection by Candida albicans in these patients. C albicans also reside in the gastrointestinal tract as a commensal fungus. However, the contribution of gut-derived C albicans in non-access-related infections in kidney disease is unknown. Using a mouse model of kidney disease, we demonstrate that uremic animals showed increased gut barrier permeability, impaired mucosal defense, and dysbiosis. The disturbance in gut homeostasis is sufficient to drive the translocation of microbiota and intestinal pathogen Citrobacter rodentium to extraintestinal sites but not C albicans Interestingly, a majority of uremic animals showed fungal translocation only when the gut barrier integrity is disrupted. Our data demonstrate that uremia coupled with gut mucosal damage may aid in the translocation of C. albicans and cause systemic infection in kidney disease. Because most of the individuals with kidney disease suffer from some form of gut mucosal damage, these results have important implications in the risk stratification and control of non-access-related opportunistic fungal infections in these patients.

Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization.

Chronic kidney disease (CKD) affects more than 10% of the world population and leads to excess morbidity and mortality (with cardiovascular disease as a leading cause of death). Vascular calcification (VC) is a phenomenon of disseminated deposition of mineral content within the media layer of arteries preceded by phenotypic changes in vascular smooth muscle cells (VSMC) and/or accumulation of mineral content within the atherosclerotic lesions. Medial VC results in vascular stiffness and significantly contributes to increased cardio-vascular (CV) morbidity, whereas VC of plaques may rather increase their stability. Mineral and bone disorders of CKD (CKD-MBD) contribute to VC, which is further aggravated by accumulation of uremic toxins. Both CKD-MBD and uremic toxin accumulation affect not only patients with advanced CKD (glomerular filtration rate (GFR) less than 15 mL/min./1.72 m2, end-stage kidney disease) but also those on earlier stages of a disease. The key uremic toxins that contribute to VC, i.e., p-cresyl sulphate (PCS), indoxyl sulphate (IS) and trimethylamine-N-oxide (TMAO) originate from bacterial metabolism of gut microbiota. All mentioned toxins promote VC by several mechanisms, including: Transdifferentiation and apoptosis of VSMC, dysfunction of endothelial cells, oxidative stress, interaction with local renin-angiotensin-aldosterone system or miRNA profile modification. Several attractive methods of gut microbiota manipulations have been proposed in order to modify their metabolism and to limit vascular damage (and VC) triggered by uremic toxins. Unfortunately, to date no such method was demonstrated to be effective at the level of "hard" patient-oriented or even clinically relevant surrogate endpoints.