Changes in intestinal barriers with an increased intestinal permeability is common in CKD (Table 2).

Increasing urea levels and expanding bacteria with urease causes an increase ammonium production in the intestinal lumen and induce changes in intestinal pH that produces an alteration of intestinal permeability by affecting the tight junctions of the enterocyte. Vaziri et al. have demonstrated a marked reduction of tight junction proteins, claudin-1, occludin, and ZO1, in the colonic mucosa in CKD; this is associated with an infiltration of mononuclear leukocytes in the lamina propria and a marked thickening of the colon wall.33 There is histological evidence of chronic inflammation of the intestinal tract including oesophagitis, gastritis, etc.33,34

The presence of frequent oedema and hypervolaemia in CKD may aggravate intestinal barrier dysfunction in CKD patients on, haemodialysis, or peritoneal dialysis. In addition, excessive ultrafiltration and episodes of hypotension during haemodialysis may cause episodes of transient intestinal ischaemia which increases the permeability of the intestinal barrier facilitating the passage of endotoxins.33

In renal transplant patients, the investigation of the gut microbiota is in its infancy. It is known that inflammatory processes, such as graft ischaemia time, baseline disease and immunosuppressive drugs may play a relevant role in the alteration of the intestinal barrier.35,36

In CKD, the decreased clearance of proinflammatory cytokines, is associated with the development of oxidative stress and inflammation. The later are contributing factors to the progression of the disease and its complications, including cardiovascular disease, cachexia, and anaemia. Oxidative stress and chronic inflammation stimulate the NF-κB transcription factor, which is the key regulator of proinflammatory cytokines and chemokines. Increased permeability of intestinal barriers in CKD patients favours the translocation of bacterial products of intestinal origin, as evidenced by the presence of DNA fragments of circulating intestinal pathogens (aerobic and anaerobic), both in patients in different stages of CKD and on renal replacement therapy.37–39 The increase in circulating bacterial products of intestinal origin activates innate immunity, promotes the inflammatory state associated with CKD and, increases the incidence of cardiovascular disease and mortality.40–42

In recent years there is a growing interest in restoring the symbiosis of intestinal microflora in CKD aiming to reduce the generation of uraemic toxins, oxidative stress, and inflammation.79

• a)

  High fibre diet: a high fibre diet increases the production of SCFA, which provides energy to the intestinal flora and allows amino acids that reach the colon to be incorporated into bacterial proteins and be excreted instead of being fermented into uraemic solutes. In addition, SCFAs are used as substrate by the intestinal mucosa helping to maintain their functionality and integrity. Fibre increases intestinal transit reducing the time for fermentation of amino acids and improves the composition of microflora which reduces the production of undesirable solutes. In CKD patients, there is a direct relationship between dietary protein/fibre ratio and PCS and IS levels, so a diet with a low protein/fibre ratio should be beneficial.80 In healthy subjects, a vegetarian diet, as compared with the omnivore diet, reduces the generation IS or PCS; this effect was related to the higher fibre and lower protein content of the vegetarian diet.81 A very low protein diet (0.3g/kg body weight/day) supplemented with amino acid keto-analogues also reduces IS levels in patients with CKD.82

  Several therapeutic interventions have recently explored to improve the dysbiosis of the intestinal microflora, reduce the absorption of uraemic toxins and the passage of endotoxins from the intestinal lumen.

• b)

  Prebiotics, probiotics, and symbiotics: the generation of uraemic toxins could be reduced by selectively increasing saccharolyticbacteria (which digest dietary fibre) and decreasing proteolytic bacteria (protein and amino acid fermenters) in the colon. The main regulator of metabolism of colon bacteria is the availability of nutrients and specifically the rate of fermentable carbohydrates vs. nitrogen.

  Prebiotics are non-digestible food components which, through selective fermentation, allow for specific changes in the composition or activity in gastrointestinal microflora, which are beneficial to the health and well-being of the host. Prebiotics stimulate the growth or activity of one or a limited number of bacteria in the colon; they may increase carbohydrate fermentables vs. nitrogen; they include inulin, fructooligosaccharides, galactooligosaccharides, etc. Inulin enriched with oligofructose reduces the generation of PCS and the serum concentrations in hemodialysis patients, but has no effect on IS.83 Resistant starch reduces IS levels in hemodialysis patients and reduces PCS but not significantly.84 In a CKD rat model, a diet rich in resistant starch delayed the progression of CKD and attenuated oxidative stress and inflammation.85 Currently, a randomised, crossover, double-blind, phase 2 clinical trial in patients with stage 3b-4 CKD is examining the effect of the supplementation of arabinoxylan-oligosaccharides on plasma levels of PCS and indole derivatives urinary excretion of these compounds and insulin resistance are also examined.86

  Probiotics are defined as “living micro-organisms” that, being administered in adequate amounts, provide a health benefit to the host. A recent review evaluates the potential benefits of probiotics in general and especially in CKD.87 The efficacy of probiotics to decrease levels of uraemic toxins and to delay the progression of CKD has been investigated in in vitro models, animal models and in patients with CKD. However, to date, there are no large-scale quality intervention studies and studies on clinical events to support their widespread use. There are only small studies, most of which,88,92–95 but not all,97 observe a decrease in uraemic toxin levels. Administration of Bifidobacterium longum in enteric capsules to patients with CKD had minimal effects on the progression of the disease in patients with CKD.91 However, a randomised, double-blind trial in patients on peritoneal dialysis observed a significant reduction in serum proinflammatory endotoxin and cytokine levels, an increase in serum IL-10 levels, and the preservation of residual renal function after 6 months of treatment with a probiotic96 (Table 4).

  Table 4.

  Clinical studies with probiotics in patients with CKD and their effects.

  Author and year	Probiotic	Type of study	Results
  Hida et al., 199688	Lebenin	Observational, patients in HD (n=25), 4 weeks	↓ Indicate in faeces and serum ↓ p-Cresol in faeces
  Simenhoff et al., 199689	Lactobacillus acidophilus	Observational, patients in HD (n=8)	↓ Dimethylamine ↓ Nitrosodimethylamine
  Takayama et al., 200390	Bifidobacterium longum JCM008	Non-randomised, placebo-controlled. Patients in HD (n=22), 5 weeks	↓ Indoxyl sulfate
  Ando et al., 200391	Bifidobacterium longum	Observational, patients with CKD (n=27), 6 months	Reduction of the progression of CKD in patients with con Cr ≥4mg/dl or P≥4mg/dl
  Taki et al., 200592	Bifidobacterium longum	Non-randomised, placebo-controlled. Patients in HD (n=27), 12 weeks	↓ Indoxyl sulfate, homocysteine and triglycerides
  Ranganathan et al., 200993	Lactobacillus acidophilus KB31, Streptococcus thermophilus KB27, Bifidobacterium longum KB35	Randomised, double-blind, crossover, placebo-controlled. Patients with CKD 3–4 (n=16), 6 months	BUN Uric acid ↑ Quality of life
  Ranganathan et al., 201094	Lactobacillus acidophilus KB31, Streptococcus thermophilus KB27, Bifidobacterium longum KB35	Multicentre, randomised, double-blind, placebo-controlled. Patients with CKD 3–4 (n=46), 6 months	BUN ↑ Quality of life Insurance
  Miranda Alatriste et al., 201495	Lactobacillus casei shirota	Randomised, placebo-controlled, patients with CKD 3–4 (n=30), 8 weeks	↓ Urea
  Wang et al., 201596	Bifidobacterium bifidum A218, Bifidobacterium catenulatum A302, Bifidobacterium longum A101, Lactobacillus plantarum A87	Randomised, double-blind, placebo-controlled, patients in PD (n=39), 6 months	↓ TNF-α, IL-5, IL-6 and endotoxin ↑ IL-10 Residual preservation of kidney function
  Natarajan et al., 201497	Renadyl	Randomised, double-blind, placebo-controlled, patients in HD (n=22), 8 weeks	No changes in quality of life Tendency towards reduction of indoxyl glucuronide, CRP and leucocyte count

  Cr, creatinine; PD, peritoneal dialysis; CKD, chronic kidney disease; HD, haemodialysis; IL, interleukin; P, phosphorus; CRP, C-reactive protein.

  Symbiotics are probiotic supplements combined with prebiotics. In hemodialysis patients, on treatment with a symbiotic there is a decrease in the level of PCS, but not those of IS,98 which was confirmed in another study.102 Another study observed a delay in the progression of CKD with symbiotic treatment,100 while another study did not observe a significant improvement in inflammation markers.103 Finally, a randomised, double-blind, crossover study in patients with CKD104 demonstrated a reduction in PCS levels, a non-significant decrease in IS and an increase in bifidobacteria and reduction of faecal ruminococcus, but no change in inflammation markers, oxidative stress, or endotoxins, although a slight increase in albuminuria was observed (Table 5).

  Table 5.

  Clinical studies with symbiotics in patients with CKD and their effects.

  Author and year	Symbiotic	Study	Results
  Nakabayashi et al., 201098	Lactobacillus casei shirota, Bifidobacterium breve yakult and galactooligosaccharides	Observational, patients in HD (n=9), 4 weeks	↓ p-Cresol in plasma Normalisation of bowel habits Association of p-cresol and constipation
  Ogawa et al., 201299	Bifidobacterium longum JBL01 and oligosaccharides	Observational, patients in HD (n=15). Control group patients in HD (n=16), 4 weeks	↓ P levels that returned to baseline 2 weeks later
  Pavan et al., 2014100	Probiotic and prebiotic	Prospective, open, randomised, placebo-controlled. Patients with CKD 3–5 (n=24), 12 months	Reduction in the progression of CKD
  Cruz-Mora et al., 2014101	Lactobacillus acidophilus, Bifidobacterium lactis and inulin	Double-blind, randomised, placebo-controlled. Patients in HD (n=18), 2 months	↑ Bifidobacteria in faeces ↓ Lactobacilli in faeces (in the 2 groups) Improvements of GI symptoms
  Guida et al., 2014102	Lactobacillus plantarum, Lactobacillus casei subsp. Rhamnosus, Lactobacillus gasseri, Bifidobacterium infantis, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus salivarius, Lactobacillus sporogenes and Streptococcus thermophilus inulin and resistant tapioca starch	Randomised, double-blind, placebo-controlled. Patients with CKD 3–4 (n=30), 4 weeks	↓ p-Cresol in plasma With no changes in GI symptoms
  Viramontes-Hörner et al., 2015103	Lactobacillus acidophilus and Bifidobacterium lactis+prebiotic (inulin)	Randomised, double-blind, placebo-controlled. Patients in HD (n=42), 2 months	Tendency to diminish levels of CRP and TNF-α. Improvement of GI symptoms
  Rossi et al., 2014104	Lactobacillus, bifidobacteria and Streptococcus generates+inulin, fructooligosaccharides and galactooligosaccharides	Randomised, double-blind, crossover, placebo-controlled. Patients with CKD 4–5, 6 weeks with a washout of 4 weeks	Decreased PCS, decreased NS of IS Increased bifidobacteria and decreased ruminococcaceae in faeces. No changes in oxidative stress or inflammation markers and slight increase in albuminuria

  CRD, chronic kidney disease; GI, gastrointestinal; HD, haemodialysis; NO, nonsignificant; P, phosphorus; CRP, C-reactive protein; PCS, p-cresyl sulfate.

  One of the major limitations of probiotic or symbiotic therapy is that no study has yet demonstrated the sustained survival of probiotics in the dysbiotic colon of patients with CKD. There are also no studies that have evaluated the effect of these treatments on the levels of TMAO in this population. In choosing probiotics, the contribution of urease-containing bacteria must be considered, since they may increase intestinal ammonia generation, which may damage epithelial tight junctions, and increase intestinal permeability to the passage of endotoxins from the intestinal lumen.33,34

• c)

  Adsorptive therapies: the use of oral sorbents could decrease uraemic toxins and circulating intestinal endotoxins. AST-120 oral sorbents decrease IS levels in a dose-dependent manner.105 In addition, a reduction in the IS, PCS, or phenyl sulfate and oxidative stress levels have been described in patients on haemodialysis.106 Other authors have reported that the administration of AST-120 improves the erythropoietic response to CERA.107 AST-120 improves intestinal barrier dysfunction and decreases endotoxin plasma levels, inflammation markers and oxidative stress in a CKD model in rats.108

Although small randomised, controlled studies in experimental animals and retrospective studies in patients have indicated a nephroprotective effect of AST-120 (reviewed by Schulman et al.109), a subsequent large randomised, controlled trial in patients with CKD was unable to confirm this.109 The study had some methodological limitations, but also suggested the possibility that the objective of treating specific uraemic toxins may not be sufficient. However, another retrospective study of the long-term effects of AST-120 on patients with stage 3–5 CKD showed a reduction in the risk of progression to dialysis, mortality, cardiac events and vascular accident vs. those patients who did not receive it.110

Although a beneficial effect of sevelamer on IS and PCS has been described in in vitro studies, in vivo studies in mice or patients have not demonstrated a reduction in the levels of these uraemic toxins.111 However, sevelamer does reduce endotoxin levels and systemic inflammation in patients on haemodialysis.112,113

• 1.

  In CKD, there is a dysbiosis of the intestinal microflora.

• 2.

  Intestinal microflora generate uraemic toxins that are absorbed and accumulate in CKD, and are associated with increased oxidative stress and inflammation.

• 3.

  In CKD, there is an increase in the permeability of the intestinal barrier that allows the passage into the systemic circulation of endotoxins and other bacterial products that aggravate the inflammatory state of CKD.

• 4.

  Changes in diet composition could improve microflora dysbiosis in CKD, reduce uraemic toxin levels, or restore intestinal mucosal permeability in CKD patients.

• 5.

  The use of probiotics, prebiotics or symbiotics opens an alternative in the treatment of intestinal dysbiosis associated with CKD, and may play a role in slowing the progression of CKD and in preventing relevant associated complications such as mortality and cardiovascular risk.