Advertisement

Gut Endothelial Leakage of Endotoxin May Be the Source of Vascular Inflammation and Injury in CKD. How Can This Be Targeted?

  • Niti Madan
    Affiliations
    Division of Nephrology, Department of Medicine, University of California Davis School of Medicine, Davis, California
    Search for articles by this author
  • George A. Kaysen
    Correspondence
    Address correspondence to George A. Kaysen, MD, PhD, Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Davis, CA 95616.
    Affiliations
    Division of Nephrology, Department of Medicine, University of California Davis School of Medicine, Davis, California

    Department of Biochemistry and Molecular Medicine, University of California Davis School of Medicine, Davis, California
    Search for articles by this author
      Related Articles, p. 13 and p. 28
      The risk of cardiovascular events increases as glomerular filtration rate declines increasing as much as 35 fold in patients with Stage 5 chronic kidney disease (CKD).
      • Go A.S.
      • Chertow G.M.
      • Fan D.
      • McCulloch C.E.
      • Hsu C.Y.
      Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
      Despite the vast increase in risk in this population, biomarkers associated with risk in the general population, such as cholesterol level contribute little risk,
      • Lowrie E.G.
      • Lew N.L.
      Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities.
      while the primary biomarkers associated with increased risk are those linked to inflammation.
      • Johansen K.L.
      • Young B.
      • Kaysen G.A.
      • Chertow G.M.
      Association of body size with outcomes among patients beginning dialysis.
      • Yeun J.Y.
      • Levine R.A.
      • Mantadilok V.
      • Kaysen G.A.
      C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.
      One open question is identifying the causal pathway between inflammatory biomarkers, which themselves may simply provide evidence of inflammation and vascular injury. The risk of adverse cardiovascular outcomes is significantly increased even among individuals with normal renal function after an infectious event.
      • Smeeth L.
      • Thomas S.L.
      • Hall A.J.
      • Hubbard R.
      • Farrington P.
      • Vallance P.
      Risk of myocardial infarction and stroke after acute infection or vaccination.
      Acute infectious events are followed by changes in vascular structure, specifically an increase in carotid intima-media thickening, even among children after an infection
      • Liuba P.
      • Persson J.
      • Luoma J.
      • Ylä-Herttuala S.
      • Pesonen E.
      Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media.
      suggesting that inflammation, rather than being a consequence of vascular injury, is on the causal pathway. Inflammation, as measured by C-reactive protein (CRP), by other acute phase proteins or by cytokine levels, is increased well above the general population,
      • Honda H.
      • Qureshi A.R.
      • Heimbürger O.
      • et al.
      Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD.
      even in the absence of obvious prior infectious event among patients with CKD.
      • Kimmel P.L.
      • Phillips T.M.
      • Simmens S.J.
      • et al.
      Immunologic function and survival in hemodialysis patients.
      CRP has been previously reported to be increased in patients with kidney transplants and to be associated with cardiovascular outcomes.
      • Ocak N.
      • Dirican M.
      • Ersoy A.
      • Sarandol E.
      Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure.
      The question addressed in this issue of the Journal by Chan et al
      • Chan W.
      • Bosch J.A.
      • Phillips A.C.
      • Chin S.H.
      The associations of endotoxemia with systemic inflammation, endothelial activation, and cardiovascular outcome in kidney transplantation.
      is identification of endotoxin absorbed through the gut mucosa as 1 potential sources of inflammation in this population as well as linking this to vascular injury and cardiovascular events by its association with sE-selectin, a marker of endothelial cell activation. Ideally, this would suggest that alteration in gut wall permeability to endotoxin or its precursor, lipopolysaccharide (LPS) would provide a therapeutic target, presuming a cause and effect relationship between the biomarkers studies and the causal pathway to injury. Of note, while CRP is indeed highly associated with vascular risk, this acute phase protein may well not be on the causal pathway, but instead reflect an inflammatory response
      • Panichi V.
      • Maggiore U.
      • Taccola D.
      • et al.
      Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.
      in which cytokines or the inciting inflammatory event, such as LPS or endotoxin causes vascular injury. Chan et al.
      • Chan W.
      • Bosch J.A.
      • Phillips A.C.
      • Chin S.H.
      The associations of endotoxemia with systemic inflammation, endothelial activation, and cardiovascular outcome in kidney transplantation.
      identify a number of factors, including circulating endotoxin as well as factors associated with body composition and nutrition that were associated both with CRP as well as the endothelial marker sE-selectin, a biomarker associated with endothelial health and vascular injury in other populations.
      • Manco M.
      • Nobili V.
      • Alisi A.
      • Panera N.
      • Handberg A.
      Arterial stiffness, thickness and association to suitable novel markers of risk at the origin of cardiovascular disease in obese children.
      Adiposity, another source of pro-inflammatory cytokines
      • Delgado C.
      • Chertow G.M.
      • Kaysen G.A.
      • et al.
      Associations of body mass index and body fat with markers of inflammation and nutrition among patients receiving hemodialysis.
      was also associated with sE-selectin, as was 25 OH vitamin D, noted to be associated both with LPS level and the composition of gut bacterial composition.
      • Luthold R.V.
      • Fernandes G.R.
      • Franco-de-Moraes A.C.
      • Folchetti L.G.
      • Ferreira S.R.
      Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals.
      One important target identified
      • Chan W.
      • Bosch J.A.
      • Phillips A.C.
      • Chin S.H.
      The associations of endotoxemia with systemic inflammation, endothelial activation, and cardiovascular outcome in kidney transplantation.
      that could possibly be altered is the source of endotoxin—a lipid of bacterial origin that itself induces endothelial damage.
      • Hauser A.B.
      • Stinghen A.E.
      • Goncalves S.M.
      • Bucharles S.
      • Pecoits- Filho R.
      A gut feeling on endotoxemia: causes and consequences in chronic kidney disease.
      Endotoxin was identified both as a close correlate to CRP, but also to sE-selectin levels, a marker of endothelial injury, and adverse outcome. Alteration in gut wall permeability is an obvious target and the observation that increased fructose intake and decreased fibrin intake were also associated with inflammation, suggest that affecting gut wall permeability by dietary modification or some other process may be effective in reducing cardiovascular events by reducing exposure to endotoxins. Since changes in dietary patterns and changes within individuals or populations have been associated with changes in the gut microbiome,
      • Smits S.A.
      • Leach J.
      • Sonnenburg E.D.
      • et al.
      Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania.
      • David L.A.
      • Maurice C.F.
      • Carmody R.N.
      • et al.
      Diet rapidly and reproducibly alters the human gut microbiome.
      dietary changes designed to effect a change in the microbiome could prove effective in altering gut permeability to toxins. CKD results in profound changes in the composition of the gut microbiome and in disruption of the intestinal epithelial barrier structure and function.
      • Rossi M.
      • Johnson D.W.
      • Campbell K.L.
      The kidney-gut axis: implications for nutrition care.
      • Vaziri N.D.
      • Wong J.
      • Pahl M.
      • et al.
      Chronic kidney disease alters intestinal microbial flora.
      Two strategies may be used to accomplish change in the microbiome. One is a change in diet and the other is the administration of probiotic bacteria
      • Takayama F.
      • Taki K.
      • Niwa T.
      Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis.
      • El Hage R.
      • Hernandez-Sanabria E.
      • Van de Wiele T.
      Emerging trends in “Smart probiotics”: functional consideration for the development of novel health and industrial applications.
      although affecting a change in gut flora by administration of probiotics may be challenging.
      • El Hage R.
      • Hernandez-Sanabria E.
      • Van de Wiele T.
      Emerging trends in “Smart probiotics”: functional consideration for the development of novel health and industrial applications.
      The recommended diet for patients with CKD is low in potassium, phosphorous, and as a consequence, low in plant fiber and symbiotic organisms altering the normal gut microbiome resulting in higher number of pathogens like clostridia, enterobacteria, pseudomonas, and a lower number of beneficial microbes like lactobacilli and bifidobacteria.
      • Vaziri N.D.
      • Wong J.
      • Pahl M.
      • et al.
      Chronic kidney disease alters intestinal microbial flora.
      • Suarez J.E.
      [Autochthonous microbiota, probiotics and prebiotics].
      • Chassard C.
      • Lacroix C.
      Carbohydrates and the human gut microbiota.
      • Cigarran Guldris S.
      • Gonzalez Parra E.
      • Cases Amenos A.
      Gut microbiota in chronic kidney disease.
      The alteration in the gut microbiome results in the production of uremic toxins like advanced glycation products, phenols, and indoles which are then converted to indole-3 acetic acid, indoxyl sulfate (IS), and p-cresyl sulfates, glucuronides,
      • Hasegawa S.
      • Jao T.M.
      • Inagi R.
      Dietary metabolites and chronic kidney disease.
      • Borges N.A.
      • Carmo F.L.
      • Stockler-Pinto M.B.
      • et al.
      Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial.
      which are associated with the levels of inflammatory biomarkers.
      • Borges N.A.
      • Barros A.F.
      • Nakao L.S.
      • Dolenga C.J.
      • Fouque D.
      • Mafra D.
      Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease.
      This leads to generation and absorption trimethylamine (TMA), which is converted to potentially harmful TMA oxide (TMAO) by the liver. While TMAO is associated with vascular injury in non-CKD patient populations
      • Qi J.
      • You T.
      • Li J.
      • et al.
      Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies.
      and while levels are greatly elevated among dialysis patients, there does not appear to be an association between TMAO levels and cardiovascular outcome or inflammation in dialysis patients,
      • Kaysen G.A.
      • Johansen K.L.
      • Chertow G.M.
      • et al.
      Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis.
      similar to what is observed for low-density lipoprotein cholesterol levels.
      • Lowrie E.G.
      • Lew N.L.
      Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities.
      • Kilpatrick R.D.
      • McAllister C.J.
      • Kovesdy C.P.
      • Derose S.F.
      • Kopple J.D.
      • Kalantar-Zadeh K.
      Association between serum lipids and survival in hemodialysis patients and impact of race.
      If the pathway to vascular injury is mediated by endotoxin directly and can be altered by changing gut wall permeability, alteration in gut flora may provide a therapeutic target.
      Also in this issue of the Journal, Borges et al
      • Borges N.A.
      • Carmo F.L.
      • Stockler-Pinto M.B.
      • et al.
      Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial.
      used probiotic supplementation to alter the gut flora in dialysis patients. They found that uremic toxins, inflammatory markers, and gut profile were not altered. In addition, serum potassium, urea, and IS were increased. This was a double-blind, randomized, placebo-controlled trial enrolling 46 hemodialysis patients of whom 23 received probiotics (Streptococcus thermophilus, Lactobacillus acidophilus, and Bifidobacteria longum) daily for 3 months and 23 received placebo. No change was observed in gut microbiota profile after probiotic or placebo supplementation. Studies in the past have shown benefits of probiotics in CKD population,
      • Ranganathan N.
      • Ranganathan P.
      • Friedman E.A.
      • et al.
      Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease.
      • Miranda Alatriste P.V.
      • Urbina Arronte R.
      • Gomez Espinosa C.O.
      • Espinosa Cuevas Mde L.
      Effect of probiotics on human blood urea levels in patients with chronic renal failure.
      and at same time, some studies have shown negative results.
      • Natarajan R.
      • Pechenyak B.
      • Vyas U.
      • et al.
      Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients.
      • Vaziri N.D.
      • Zhao Y.Y.
      • Pahl M.V.
      Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.
      • Vaziri N.D.
      CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity.
      One explanation for negative results may be that high urea levels in the colon lumen promote biochemical alterations in the colonic environment.
      • Natarajan R.
      • Pechenyak B.
      • Vyas U.
      • et al.
      Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients.
      • Vaziri N.D.
      • Zhao Y.Y.
      • Pahl M.V.
      Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.
      • Mafra D.
      • Lobo J.C.
      • Barros A.F.
      • Koppe L.
      • Vaziri N.D.
      • Fouque D.
      Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease.
      These alterations may alter enzymatic activity of bacteria including probiotics providing a greater urea hydrolysis rate and large amounts of ammonia. Part of the ammonia may be absorbed reaching the intrahepatic portal circulation and enter the urea cycle, thereby increasing ureagenesis. In addition, ammonia may be converted to ammonium hydroxide, increasing intestinal permeability. Damage to the intestinal barrier could affect the gastrointestinal excretion of potassium and increase membrane permeability to the diffusion of substances (such as IS) from the intestinal lumen into the blood. This may result in worsening of systemic inflammation. In the study of Borget et al., IS levels were increased but other toxins (p-cresyl sulfate and indole-3 acetic acid) showed no significant change.
      Prebiotics may contribute to modulation of the gut microbiota and to improve integrity of intestinal epithelial barrier thus promoting more favorable scenario for the introduction of probiotic microorganisms.
      • Moraes C.
      • Borges N.A.
      • Mafra D.
      Resistant starch for modulation of gut microbiota: promising adjuvant therapy for chronic kidney disease patients?.
      Besides prebiotics, other strategies like physical activity and oral adsorbents may improve the gut imbalance in CKD. Alteration of the gut bacterial composition may require more intensive intervention than was applied or a change in diet.
      • El Hage R.
      • Hernandez-Sanabria E.
      • Van de Wiele T.
      Emerging trends in “Smart probiotics”: functional consideration for the development of novel health and industrial applications.
      • Lau W.L.
      • Vaziri N.D.
      The leaky gut and altered microbiome in chronic kidney disease.
      • Miraghajani M.
      • Zaghian N.
      • Mirlohi M.
      • Feizi A.
      • Ghiasvand R.
      The impact of probiotic soy milk consumption on oxidative stress among type 2 diabetic kidney disease patients: a randomized controlled clinical trial.
      However, the study by Borges et al.
      • Borges N.A.
      • Carmo F.L.
      • Stockler-Pinto M.B.
      • et al.
      Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial.
      has a small sample size, inflammatory markers could be influenced by other factors, and food intake was not monitored. A larger study is needed before this approach can be excluded. We need to remember that complexities of the gut microbiota in CKD patients should be taken into the account when probiotics are given to these patients to reestablish the gut microbiota. There are 3 theoretical safety concerns with use of probiotics: (1) occurrence of bacteremia, sepsis, or endocarditis; (2) toxic physiological or metabolic effects on the gastrointestinal tract
      • Saarela M.
      • Mogensen G.
      • Fonden R.
      • Matto J.
      • Mattila-Sandholm T.
      Probiotic bacteria: safety, functional and technological properties.
      • Senok A.C.
      • Ismaeel A.Y.
      • Botta G.A.
      Probiotics: facts and myths.
      • Henriksson A.
      • Borody T.
      • Clancy R.
      Probiotics under the regulatory microscope.
      and; (3) transfer of antibiotic resistance in the gastrointestinal flora from commensal or probiotic bacteria to other bacteria or potential pathogens.
      • Senok A.C.
      • Ismaeel A.Y.
      • Botta G.A.
      Probiotics: facts and myths.
      • Salyers A.A.
      • Gupta A.
      • Wang Y.
      Human intestinal bacteria as reservoirs for antibiotic resistance genes.
      There is theoretical risk of adverse metabolic effects from manipulation of the microbiota with the use of probiotics, even if such manipulation is temporary. The use of probiotics in clinical trials should be accompanied by data safety monitoring and knowledge of antimicrobial susceptibilities of the organism used. Other probiotic organisms, such as Enterococcus, Bacillus, and other spore-forming bacteria, streptococci, are not regarded as safe and have been used as probiotics. The most physiological path to alter the gut microbiota is a change in diet, which may be challenging to implement in this population. Nevertheless, identification of gut bacteria as the source of endotoxin, a likely source of endothelial injury, provides a convenient target for reducing the greatly increased cardiovascular risk in kidney transplant and all CKD patients. Establishing a safe, effective, and convenient therapeutic pathway to achieving this end requires further investigation.

      References

        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.Y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N Engl J Med. 2004; 351 (Erratum in: N Engl J Med. 2008;18(4):4): 1296-1305
        • Lowrie E.G.
        • Lew N.L.
        Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities.
        Am J Kidney Dis. 1990; 15: 458-482
        • Johansen K.L.
        • Young B.
        • Kaysen G.A.
        • Chertow G.M.
        Association of body size with outcomes among patients beginning dialysis.
        Am J Clin Nutr. 2004; 80: 324-332
        • Yeun J.Y.
        • Levine R.A.
        • Mantadilok V.
        • Kaysen G.A.
        C-Reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients.
        Am J Kidney Dis. 2000; 35: 469-476
        • Smeeth L.
        • Thomas S.L.
        • Hall A.J.
        • Hubbard R.
        • Farrington P.
        • Vallance P.
        Risk of myocardial infarction and stroke after acute infection or vaccination.
        N Engl J Med. 2004; 351: 2611-2618
        • Liuba P.
        • Persson J.
        • Luoma J.
        • Ylä-Herttuala S.
        • Pesonen E.
        Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media.
        Eur Heart J. 2003; 24: 515-521
        • Honda H.
        • Qureshi A.R.
        • Heimbürger O.
        • et al.
        Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD.
        Am J Kidney Dis. 2006; 47: 139-148
        • Kimmel P.L.
        • Phillips T.M.
        • Simmens S.J.
        • et al.
        Immunologic function and survival in hemodialysis patients.
        Kidney Int. 1998; 54: 236-244
        • Ocak N.
        • Dirican M.
        • Ersoy A.
        • Sarandol E.
        Adiponectin, leptin, nitric oxide, and C-reactive protein levels in kidney transplant recipients: comparison with the hemodialysis and chronic renal failure.
        Ren Fail. 2016; 38: 1639-1646
        • Chan W.
        • Bosch J.A.
        • Phillips A.C.
        • Chin S.H.
        The associations of endotoxemia with systemic inflammation, endothelial activation, and cardiovascular outcome in kidney transplantation.
        J Ren Nutr. 2017; (final citation to be populated in the same issue as this editorial)
        • Panichi V.
        • Maggiore U.
        • Taccola D.
        • et al.
        Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients.
        Nephrol Dial Transplant. 2004; 19: 1154-1160
        • Manco M.
        • Nobili V.
        • Alisi A.
        • Panera N.
        • Handberg A.
        Arterial stiffness, thickness and association to suitable novel markers of risk at the origin of cardiovascular disease in obese children.
        Int J Med Sci. 2017; 14: 711-720
        • Delgado C.
        • Chertow G.M.
        • Kaysen G.A.
        • et al.
        Associations of body mass index and body fat with markers of inflammation and nutrition among patients receiving hemodialysis.
        Am J Kidney Dis. 2017; 70: 817-825
        • Luthold R.V.
        • Fernandes G.R.
        • Franco-de-Moraes A.C.
        • Folchetti L.G.
        • Ferreira S.R.
        Gut microbiota interactions with the immunomodulatory role of vitamin D in normal individuals.
        Metabolism. 2017; 69: 76-86
        • Hauser A.B.
        • Stinghen A.E.
        • Goncalves S.M.
        • Bucharles S.
        • Pecoits- Filho R.
        A gut feeling on endotoxemia: causes and consequences in chronic kidney disease.
        Nephron Clin Pract. 2011; 118: 16
        • Smits S.A.
        • Leach J.
        • Sonnenburg E.D.
        • et al.
        Seasonal cycling in the gut microbiome of the Hadza hunter-gatherers of Tanzania.
        Science. 2017; 357: 802-806
        • David L.A.
        • Maurice C.F.
        • Carmody R.N.
        • et al.
        Diet rapidly and reproducibly alters the human gut microbiome.
        Nature. 2014; 505: 559-563
        • Rossi M.
        • Johnson D.W.
        • Campbell K.L.
        The kidney-gut axis: implications for nutrition care.
        J Ren Nutr. 2015; 25: 399-403
        • Vaziri N.D.
        • Wong J.
        • Pahl M.
        • et al.
        Chronic kidney disease alters intestinal microbial flora.
        Kidney Int. 2013; 83: 308-315
        • Takayama F.
        • Taki K.
        • Niwa T.
        Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis.
        Am J Kidney Dis. 2003; 41: S142-S145
        • El Hage R.
        • Hernandez-Sanabria E.
        • Van de Wiele T.
        Emerging trends in “Smart probiotics”: functional consideration for the development of novel health and industrial applications.
        Front Microbiol. 2017; 8: 1889
        • Suarez J.E.
        [Autochthonous microbiota, probiotics and prebiotics].
        Nutr Hosp. 2015; 31: 3-9
        • Chassard C.
        • Lacroix C.
        Carbohydrates and the human gut microbiota.
        Curr Opin Clin Nutr Metab Care. 2013; 16: 453-460
        • Cigarran Guldris S.
        • Gonzalez Parra E.
        • Cases Amenos A.
        Gut microbiota in chronic kidney disease.
        Nefrologia. 2017; 37: 9-19
        • Hasegawa S.
        • Jao T.M.
        • Inagi R.
        Dietary metabolites and chronic kidney disease.
        Nutrients. 2017; 9https://doi.org/10.3390/nu9040358
        • Borges N.A.
        • Carmo F.L.
        • Stockler-Pinto M.B.
        • et al.
        Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial.
        J Ren Nutr. 2017; (final citation to be populated in the same issue as this editorial)
        • Borges N.A.
        • Barros A.F.
        • Nakao L.S.
        • Dolenga C.J.
        • Fouque D.
        • Mafra D.
        Protein-bound uremic toxins from gut microbiota and inflammatory markers in chronic kidney disease.
        J Ren Nutr. 2016; 26: 396-400
        • Qi J.
        • You T.
        • Li J.
        • et al.
        Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies.
        J Cell Mol Med. 2017; https://doi.org/10.1111/jcmm.13307
        • Kaysen G.A.
        • Johansen K.L.
        • Chertow G.M.
        • et al.
        Associations of trimethylamine N-oxide with nutritional and inflammatory biomarkers and cardiovascular outcomes in patients new to dialysis.
        J Ren Nutr. 2015; 25: 351-356
        • Kilpatrick R.D.
        • McAllister C.J.
        • Kovesdy C.P.
        • Derose S.F.
        • Kopple J.D.
        • Kalantar-Zadeh K.
        Association between serum lipids and survival in hemodialysis patients and impact of race.
        J Am Soc Nephrol. 2007; 18: 293-303
        • Ranganathan N.
        • Ranganathan P.
        • Friedman E.A.
        • et al.
        Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease.
        Adv Ther. 2010; 27: 634-647
        • Miranda Alatriste P.V.
        • Urbina Arronte R.
        • Gomez Espinosa C.O.
        • Espinosa Cuevas Mde L.
        Effect of probiotics on human blood urea levels in patients with chronic renal failure.
        Nutr Hosp. 2014; 29: 582-590
        • Natarajan R.
        • Pechenyak B.
        • Vyas U.
        • et al.
        Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients.
        Biomed Res Int. 2014; 2014: 568571
        • Vaziri N.D.
        • Zhao Y.Y.
        • Pahl M.V.
        Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.
        Nephrol Dial Transplant. 2016; 31: 737-746
        • Vaziri N.D.
        CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity.
        Curr Opin Nephrol Hypertens. 2012; 21: 587-592
        • Mafra D.
        • Lobo J.C.
        • Barros A.F.
        • Koppe L.
        • Vaziri N.D.
        • Fouque D.
        Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease.
        Future Microbiol. 2014; 9: 399-410
        • Moraes C.
        • Borges N.A.
        • Mafra D.
        Resistant starch for modulation of gut microbiota: promising adjuvant therapy for chronic kidney disease patients?.
        Eur J Nutr. 2016; 55: 1813-1821
        • Lau W.L.
        • Vaziri N.D.
        The leaky gut and altered microbiome in chronic kidney disease.
        J Ren Nutr. 2017; 27: 458-461
        • Miraghajani M.
        • Zaghian N.
        • Mirlohi M.
        • Feizi A.
        • Ghiasvand R.
        The impact of probiotic soy milk consumption on oxidative stress among type 2 diabetic kidney disease patients: a randomized controlled clinical trial.
        J Ren Nutr. 2017; 27: 317-324
        • Saarela M.
        • Mogensen G.
        • Fonden R.
        • Matto J.
        • Mattila-Sandholm T.
        Probiotic bacteria: safety, functional and technological properties.
        J Biotechnol. 2000; 84: 197-215
        • Senok A.C.
        • Ismaeel A.Y.
        • Botta G.A.
        Probiotics: facts and myths.
        Clin Microbiol Infect. 2005; 11: 958-966
        • Henriksson A.
        • Borody T.
        • Clancy R.
        Probiotics under the regulatory microscope.
        Expert Opin Drug Saf. 2005; 4: 1135-1143
        • Salyers A.A.
        • Gupta A.
        • Wang Y.
        Human intestinal bacteria as reservoirs for antibiotic resistance genes.
        Trends Microbiol. 2004; 12: 412-416

      Linked Article