{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T17:11:03Z","timestamp":1793121063019,"version":"4.5.0"},"reference-count":118,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2018,7,11]],"date-time":"2018-07-11T00:00:00Z","timestamp":1531267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD). Numerous CVD risk factors in CKD patients have been described, but these do not fully explain the high pervasiveness of CVD or increased mortality rates in CKD patients. In CKD the loss of urinary excretory function results in the retention of various substances referred to as \u201curemic retention solutes\u201d. Many of these molecules have been found to exert toxicity on virtually all organ systems of the human body, leading to the clinical syndrome of uremia. In recent years, an increasing body of evidence has been accumulated that suggests that uremic toxins may contribute to an increased cardiovascular disease (CVD) burden associated with CKD. This review examined the evidence from several clinical and experimental studies showing an association between uremic toxins and CVD. Special emphasis is addressed on emerging data linking gut microbiota with the production of uremic toxins and the development of CKD and CVD. The biological toxicity of some uremic toxins on the myocardium and the vasculature and their possible contribution to cardiovascular injury in uremia are also discussed. Finally, various therapeutic interventions that have been applied to effectively reduce uremic toxins in patients with CKD, including dietary modifications, use of prebiotics and\/or probiotics, an oral intestinal sorbent that adsorbs uremic toxins and precursors, and innovative dialysis therapies targeting the protein-bound uremic toxins are also highlighted. Future studies are needed to determine whether these novel therapies to reduce or remove uremic toxins will reduce CVD and related cardiovascular events in the long-term in patients with chronic renal failure.<\/jats:p>","DOI":"10.3390\/toxins10070287","type":"journal-article","created":{"date-parts":[[2018,7,11]],"date-time":"2018-07-11T10:50:09Z","timestamp":1531306209000},"page":"287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Gut Microbiota and Cardiovascular Uremic Toxicities"],"prefix":"10.3390","volume":"10","author":[{"given":"Manuel T.","family":"Velasquez","sequence":"first","affiliation":[{"name":"Division of Renal Diseases and Hypertension, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Centron","sequence":"additional","affiliation":[{"name":"Division of Renal Diseases and Hypertension, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Barrows","sequence":"additional","affiliation":[{"name":"Department of Medicine, Georgetown University, Washington, DC 20007, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Dwivedi","sequence":"additional","affiliation":[{"name":"Division of Renal Diseases and Hypertension, The George Washington University, Washington, DC 20037, USA"},{"name":"United States Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic S.","family":"Raj","sequence":"additional","affiliation":[{"name":"Division of Renal Diseases and Hypertension, The George Washington University, Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S117","DOI":"10.1016\/S0272-6386(00)70239-3","article-title":"Cardiovascular disease and chronic renal disease: A new paradigm","volume":"35","author":"Sarnak","year":"2000","journal-title":"Am. J. Kidney Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa041031","article-title":"Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization","volume":"351","author":"Go","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1161\/01.CIR.0000095676.90936.80","article-title":"Kidney disease as a risk factor for development of cardiovascular disease: A statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention","volume":"108","author":"Sarnak","year":"2003","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/j.1525-139X.2008.00454.x","article-title":"Hypertrophy and fibrosis in the cardiomyopathy of uremia\u2014Beyond coronary heart disease","volume":"21","author":"Sarnak","year":"2008","journal-title":"Semin. Dial."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1053\/j.ajkd.2007.10.035","article-title":"The relationship between non-traditional risk factors and outcomes in individuals with stage 3-4 CKD","volume":"51","author":"Weiner","year":"2008","journal-title":"Am. J. Kidney Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1056\/NEJMra071313","article-title":"Uremia","volume":"357","author":"Meyer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1046\/j.1523-1755.2003.00924.x","article-title":"European Uremic Toxin Work Group (EUTox): Review on uremic toxins: Classification, concentration, and interindividual variability","volume":"63","author":"Vanholder","year":"2003","journal-title":"Kidney Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1681\/ASN.2007121377","article-title":"European Uremic Toxin Work G: A bench to bedside view of uremic toxins","volume":"19","author":"Vanholder","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1681\/ASN.2011121175","article-title":"on behalf of the European Uremic Toxin Work Group. Normal and pathologic concentrations of uremic toxins","volume":"23","author":"Duranton","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.2215\/CJN.09981110","article-title":"Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins","volume":"6","author":"Eloot","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1159\/000245639","article-title":"The gut: The forgotten organ in uremia?","volume":"29","author":"Schepers","year":"2010","journal-title":"Blood Purif."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1097\/MNH.0b013e32834b8a1d","article-title":"New insights into uremia-induced alterations in metabolic pathways","volume":"20","author":"Rhee","year":"2011","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13073-016-0296-x","article-title":"Microbial metabolism of dietary components to bioactive metabolites: Opportunities for new therapeutic interventions","volume":"8","author":"Zhang","year":"2016","journal-title":"Genome Med."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fernandez-Prado, R., Esteras, R., Perez-Gomez, M.V., Gracia-Iguacel, C., Gonzalez-Parra, E., Sanz, A.B., Ortiz, A., and Sanchez-Ni\u00f1o, M.D. (2017). Nutrients turned into toxins: Microbiota modulation of nutrient properties in chronic kidney disease. Nutrients, 9.","DOI":"10.3390\/nu9050489"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1172\/JCI103940","article-title":"Urea metabolism in man","volume":"38","author":"Walser","year":"1959","journal-title":"J. Clin Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1079\/NRR200498","article-title":"Urea nitrogen salvage mechanisms and their relevance to ruminants, non-ruminants and man","volume":"18","author":"Stewart","year":"2005","journal-title":"Nutr. Res. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1681\/ASN.2010121220","article-title":"Colonic contribution to uremic solutes","volume":"22","author":"Aronov","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/ki.2011.504","article-title":"Uremic solutes from colon microbes","volume":"81","author":"Meyer","year":"2012","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0167-4838(94)90191-0","article-title":"Involvement of l-tryptophan aminotransferase in indole-3-acetic acid biosynthesis in Enterobacter cloacae","volume":"1209","author":"Koga","year":"1994","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3249","DOI":"10.1007\/s00216-011-5436-y","article-title":"Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography-tandem mass spectrometry","volume":"401","author":"Zhu","year":"2011","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"934","DOI":"10.3390\/toxins6030934","article-title":"The aryl hydrocarbon receptor-activating effect of uremic toxins from tryptophan metabolism: A new concept to understand cardiovascular complications of chronic kidney disease","volume":"6","author":"Dou","year":"2014","journal-title":"Toxins"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Gryp, T., Vanholder, R., Vaneechoutte, M., and Griet Glorieux, G. (2017). p-Cresyl Sulfate. Toxins, 9.","DOI":"10.3390\/toxins9020052"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lin, C.J., Pan, C.F., Chuang, C.K., Sun, F.J., Wang, D.J., Chen, H.H., Liu, H.L., and Wu, C.J. (2014). p-cresyl sulfate is a valuable predictor of clinical outcomes in pre-ESRD patients. Biomed. Res. Int., 526932.","DOI":"10.1155\/2014\/526932"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"662","DOI":"10.5114\/aoms.2013.36901","article-title":"Serum p-cresyl sulfate predicts cardiovascular disease and mortality in elderly hemodialysis patients","volume":"9","author":"Lin","year":"2013","journal-title":"Arch. Med. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1038\/sj.ki.5000115","article-title":"Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients","volume":"69","author":"Bammens","year":"2006","journal-title":"Kidney Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1159\/000357641","article-title":"Effects of AST-120 on blood concentrations of protein-bound uremic toxins and biomarkers of cardiovascular risk in chronic dialysis patients","volume":"37","author":"Lee","year":"2014","journal-title":"Blood Purif."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1681\/ASN.2012050503","article-title":"p-Cresyl sulfate promotes insulin resistance associated with CKD","volume":"24","author":"Koppe","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"982","DOI":"10.2215\/CJN.12491211","article-title":"The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores","volume":"7","author":"Patel","year":"2012","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.cmet.2012.12.011","article-title":"Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation","volume":"17","author":"Bennett","year":"2013","journal-title":"Cell Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nm.3145","article-title":"Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis","volume":"19","author":"Koeth","year":"2013","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature09922","article-title":"Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease","volume":"472","author":"Wang","year":"2011","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1056\/NEJMoa1109400","article-title":"Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk","volume":"368","author":"Tang","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/nrg3182","article-title":"The human microbiome: At the interface of health and disease","volume":"13","author":"Cho","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1161\/CIRCRESAHA.115.306807","article-title":"The gut microbiome contributes to a substantial proportion of the variation in blood lipids","volume":"117","author":"Fu","year":"2015","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nri.2017.7","article-title":"Dysbiosis and the immune system","volume":"17","author":"Levy","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1136\/gutjnl-2011-301805","article-title":"A metagenomic insight into our gut\u2019s microbiome","volume":"62","author":"Lepage","year":"2013","journal-title":"Gut"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1111\/j.1753-4887.2012.00489.x","article-title":"The human microbiome: Ecosystem resilience and health","volume":"70","author":"Relman","year":"2012","journal-title":"Nutr. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/nrmicro.2017.58","article-title":"The resilience of the intestinal microbiota influences health and disease","volume":"15","author":"Sommer","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/ki.2012.345","article-title":"Chronic kidney disease alters intestinal microbial flora","volume":"83","author":"Vaziri","year":"2013","journal-title":"Kidney Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1159\/000360010","article-title":"Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD","volume":"39","author":"Wong","year":"2014","journal-title":"Am. J. Nephrol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1053\/j.ajkd.2004.04.048","article-title":"Colonic transit time in long-term dialysis patients","volume":"44","author":"Wu","year":"2004","journal-title":"Am. J. Kidney Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2196","DOI":"10.1046\/j.1523-1755.2003.00314.x","article-title":"Evidence for impaired assimilation of protein in chronic renal failure","volume":"64","author":"Bammens","year":"2003","journal-title":"Kidney Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/ki.2011.355","article-title":"High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease","volume":"81","author":"Krishnamurthy","year":"2012","journal-title":"Kidney Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1146\/annurev.micro.58.030603.123811","article-title":"Bacterial iron sources: From siderophores to hemophores","volume":"58","author":"Wandersman","year":"2004","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1099\/mic.0.040618-0","article-title":"Long-term impacts of antibiotic exposure on the human intestinal microbiota","volume":"156","author":"Jernberg","year":"2010","journal-title":"Microbiology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4554","DOI":"10.1073\/pnas.1000087107","article-title":"Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation","volume":"108","author":"Dethlefsen","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/s41467-017-00900-1","article-title":"The gut microbiome in atherosclerotic cardiovascular disease","volume":"8","author":"Jie","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/ncomms2266","article-title":"Symptomatic atherosclerosis is associated with an altered gut metagenome","volume":"3","author":"Karlsson","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1093\/ajcn\/31.9.1594","article-title":"Effects of intestinal flora on nitrogen metabolism in patients with chronic renal failure","volume":"31","author":"Mitch","year":"1978","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Barrios, C., Beaumont, M., Pallister, T., Villar, J., Goodrich, J.K., Clark, A., Pascual, J., Ley, R.E., Spector, T.D., and Bell, J.T. (2015). Gut-microbiota-metabolite axis in early renal function decline. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134311"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.kint.2017.02.011","article-title":"Evaluation of the impact of gut microbiota on uremic solute accumulation by a CE-TOFMS-based metabolomics approach","volume":"92","author":"Mishima","year":"2017","journal-title":"Kidney Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000450619","article-title":"Uremic toxin-producing gut microbiota in rats with chronic kidney disease","volume":"135","author":"Kikuchi","year":"2017","journal-title":"Nephron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.amjcard.2012.11.025","article-title":"Relation of plasma indoxyl sulfate levels and estimated glomerular filtration rate to left ventricular diastolic dysfunction","volume":"111","author":"Sato","year":"2013","journal-title":"Am. J. Cardiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1253\/circj.CJ-12-0715","article-title":"Association between indoxyl sulfate and cardiac dysfunction and prognosis in patients with dilated cardiomyopathy","volume":"77","author":"Shimazu","year":"2013","journal-title":"Circ. J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"E42","DOI":"10.25011\/cim.v36i1.19404","article-title":"Levels of indoxyl sulfate are associated with severity of coronary atherosclerosis","volume":"36","author":"Hsu","year":"2013","journal-title":"Clin. Investig. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1007\/s12012-014-9270-2","article-title":"Serum free indoxyl sulfate associated with in-stent restenosis after coronary artery stentings","volume":"15","author":"Tsai","year":"2015","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.arcmed.2012.08.002","article-title":"Indoxyl sulfate predicts cardiovascular disease and renal function deterioration in advanced chronic kidney disease","volume":"43","author":"Lin","year":"2012","journal-title":"Arch. Med. Res."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Lin, C.J., Wu, V., Wu, P.C., and Wu, C.J. (2015). Meta-analysis of the associations of p-cresyl sulfate (PCS) and indoxyl sulfate (IS) with cardiovascular events and all-cause mortality in patients with chronic renal failure. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132589"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2215\/CJN.04730514","article-title":"Association of indoxyl sulfate with heart failure among patients on hemodialysis","volume":"10","author":"Cao","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Melamed, M.L., Plantinga, L., Shafi, T., Parekh, R., Meyer, T.W., Hostetter, T.H., Coresh, J., and Powe, N.R. (2013). Retained organic solutes, patient characteristics and all-cause and cardiovascular mortality in hemodialysis: Results from the retained organic solutes and clinical outcomes (ROSCO) investigators. BMC Nephrol., 14.","DOI":"10.1186\/1471-2369-14-134"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Shafi, T., Meyer, T.W., Hostetter, T.H., Melamed, M.L., Parekh, R.S., Hwang, S., Banerjee, T., Coresh, J., and Powe, N.R. (2015). Free levels of selected organic solutes and cardiovascular morbidity and mortality in hemodialysis patients: Results from the retained organic solutes and clinical outcomes (ROSCO) investigators. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126048"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1093\/ndt\/gfq251","article-title":"Serum protein-bound uraemic toxins and clinical outcomes in haemodialysis patients","volume":"25","author":"Lin","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_63","unstructured":"Shafi, T., Sirich, T.L., Meyer, T.W., Hwang, S., Melamed, M.L., Banerjee, T., Coresh, J., Hostetter, T.H., and Powe, N.R. (2016, January 15\u201320). p-Cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine and cardiovascular outcomes in hemodialysis patients. Proceedings of the American Society Nephrology Conference Abstract, Chicago, IL, USA."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.2215\/CJN.07971109","article-title":"p-Cresol and cardiovascular risk in mild-to-moderate kidney disease","volume":"5","author":"Meijers","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/ndt\/gfr453","article-title":"Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients\u2014A prospective cohort study","volume":"27","author":"Wu","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.2215\/CJN.03980609","article-title":"European Uremic Toxin Work Group (EUTox). Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients","volume":"4","author":"Barreto","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.arcmed.2014.04.002","article-title":"Protein-bound uremic toxins, inflammation and oxidative stress: A cross-sectional study in stage 3-4 chronic kidney disease","volume":"45","author":"Rossi","year":"2014","journal-title":"Arch. Med. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1681\/ASN.2013121283","article-title":"The cardiovascular effect of the uremic solute indole-3 acetic acid","volume":"26","author":"Dou","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"E004237","DOI":"10.1161\/JAHA.116.004237","article-title":"Trimethylamine N-oxide and mortality risk in patients with peripheral artery disease","volume":"5","author":"Senthong","year":"2016","journal-title":"J. Am. Heart Assoc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"26745","DOI":"10.1038\/srep26745","article-title":"Relationship of serum trimethylamine N-oxide (TMAO) Levels with early atherosclerosis in humans","volume":"6","author":"Randrianarisoa","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_71","first-page":"194","article-title":"Potential uremic toxins modulate energy metabolism of cardiac myocytes in vitro","volume":"5","author":"Weisensee","year":"1997","journal-title":"Exp. Nephrol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.tox.2012.07.004","article-title":"Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes","volume":"302","author":"Peng","year":"2012","journal-title":"Toxicology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1016\/j.lfs.2013.05.008","article-title":"Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats","volume":"92","author":"Yisireyili","year":"2013","journal-title":"Life Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.toxlet.2015.01.021","article-title":"Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting of the AMPK\/UCP2 signaling pathway","volume":"234","author":"Yang","year":"2015","journal-title":"Toxicol. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Lekawanvijit, S., Kompa, A.R., Manabe, M., Wang, B.H., Langham, R.G., Nishijima F Kelly, D.J., and Krum, H. (2012). Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041281"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.toxlet.2016.12.017","article-title":"Trimethylamine N-oxide impairs pyruvate and fatty acid oxidation in cardiac mitochondria","volume":"267","author":"Volska","year":"2017","journal-title":"Toxicol. Lett."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.atherosclerosis.2015.01.034","article-title":"Urea-induced ROS cause endothelial dysfunction in chronic renal failure","volume":"239","author":"Du","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"S102","DOI":"10.1046\/j.1523-1755.2001.59780102.x","article-title":"Carbamoylation of amino acids and proteins in uremia","volume":"78","author":"Kraus","year":"2001","journal-title":"Kidney Int."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/nm1637","article-title":"Protein carbamylation links inflammation, smoking, uremia and atherogenesis","volume":"13","author":"Wang","year":"2007","journal-title":"Nat. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/ki.2015.166","article-title":"Protein carbamylation and cardiovascular disease","volume":"88","author":"Verbrugge","year":"2015","journal-title":"Kidney Int."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1681\/ASN.2012030254","article-title":"Protein carbamylation predicts mortality in ESRD","volume":"24","author":"Koeth","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/j.1523-1755.2004.00399.x","article-title":"The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair","volume":"65","author":"Dou","year":"2004","journal-title":"Kidney Int."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1111\/j.1538-7836.2007.02540.x","article-title":"The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells","volume":"5","author":"Dou","year":"2007","journal-title":"J. Thromb. Haemost."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1038\/sj.ki.5000340","article-title":"Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells","volume":"69","author":"Yamamoto","year":"2006","journal-title":"Kidney Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1681\/ASN.2012030281","article-title":"Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall","volume":"24","author":"Pletinck","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.bbrc.2016.11.017","article-title":"Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via","volume":"481","author":"Sun","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1097\/01.ASN.0000106014.20274.C7","article-title":"Diets for patients with chronic kidney disease, still worth prescribing","volume":"15","author":"Mitch","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1146\/annurev-nutr-080508-141051","article-title":"Navigating between the Scylla and Charybdis of prescribing dietary protein for chronic kidney diseases","volume":"29","author":"Franch","year":"2009","journal-title":"Annu. Rev. Nutr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1017\/S0007114510003363","article-title":"Prebiotic effects: Metabolic and health benefits","volume":"104","author":"Roberfroid","year":"2010","journal-title":"Br. J. Nutr."},{"key":"ref_90","first-page":"1","article-title":"The composition and metabolism of faecal microbiota is specifically modulated by different dietary polysaccharides and mucin: An isothermal microcalorimetry study","volume":"12","author":"Adamberg","year":"2017","journal-title":"Benef. Microbes"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Vaziri, N.D., Liu, S.M., Lau, W.L., Khazaeli, M., Nazertehrani, S., Farzaneh, S.H., Kieffer, D.A., Adams, S.H., and Martin, R.J. (2014). High amylose resistant starch diet ameliorates oxidative stress, inflammation, and progression of chronic kidney disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114881"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"F857","DOI":"10.1152\/ajprenal.00513.2015","article-title":"Resistant starch alters gut microbiome and metabolomic profiles concurrent with amelioration of chronic kidney disease in rats","volume":"310","author":"Kieffer","year":"2016","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1053\/j.jrn.2012.04.002","article-title":"Foods with added fiber lower serum creatinine levels in patients with chronic kidney disease","volume":"23","author":"Salmean","year":"2013","journal-title":"J. Ren. Nutr."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/ndt\/gfp414","article-title":"p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin","volume":"25","author":"Meijers","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.2215\/CJN.00490114","article-title":"Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients","volume":"9","author":"Sirich","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"568571","DOI":"10.1155\/2014\/568571","article-title":"Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients","volume":"2014","author":"Natarajan","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3920\/BM2014.0088","article-title":"The effect of probiotics on serum levels of cytokine and endotoxin in peritoneal dialysis patients: A randomised, double-blind, placebo-controlled trial","volume":"6","author":"Wang","year":"2015","journal-title":"Benef. Microbes"},{"key":"ref_98","first-page":"92","article-title":"Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus","volume":"22","author":"Simenhoff","year":"1996","journal-title":"Miner. Electrolyte Metab."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"S142","DOI":"10.1053\/ajkd.2003.50104","article-title":"Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis","volume":"41","author":"Takayama","year":"2003","journal-title":"Am. J. Kidney Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1100\/tsw.2005.86","article-title":"Probiotic amelioration of azotemia in 5\/6th nephrectomized Sprague-Dawley rats","volume":"5","author":"Ranganathan","year":"2005","journal-title":"Sci. World J."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.numecd.2014.04.007","article-title":"Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: A randomized clinical trial","volume":"24","author":"Guida","year":"2014","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2215\/CJN.05240515","article-title":"Synbiotics easing renal failure by improving gut microbiology (SYNERGY): A randomized trial","volume":"11","author":"Rossi","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.1744-9987.2007.00430.x","article-title":"AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases","volume":"11","author":"Ueda","year":"2007","journal-title":"Ther. Apheresis Dial."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1159\/000077536","article-title":"Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure","volume":"27","author":"Nakamura","year":"2004","journal-title":"Kidney Blood Press. Res."},{"key":"ref_105","first-page":"535","article-title":"Cardiorenal protective effect of the oral uremic toxin ABSORBENT AST-120 in chronic heart disease patients with moderate CKD","volume":"23","author":"Shibahara","year":"2010","journal-title":"J. Nephrol."},{"key":"ref_106","first-page":"S188","article-title":"Effects of oral adsorbent AST-120 on the progression of chronic renal failure: A randomized controlled study. Effects of oral adsorbent AST-120 on the progression of chronic renal failure: A randomized controlled study","volume":"63","author":"Owada","year":"1997","journal-title":"Kidney Int. Suppl."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nm0896-883","article-title":"Microencapsulated genetically engineered live, E. coli DH5 cells administered orally to maintain normal plasma urea level in uremic rats","volume":"2","author":"Prakash","year":"1996","journal-title":"Nat. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.chom.2016.10.021","article-title":"Modulation of a Circulating Uremic Solute via Rational Genetic Manipulation of the Gut Microbiota","volume":"20","author":"Devlin","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1681\/ASN.2012080875","article-title":"High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients","volume":"24","author":"Maduell","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1093\/ndt\/gfv349","article-title":"HDF Pooling Project Investigators. Haemodiafiltration and mortality in end-stage kidney disease patients: A pooled individual participant data analysis from four randomized controlled trials","volume":"31","author":"Peters","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"18448","DOI":"10.1038\/srep18448","article-title":"MCO Membranes: Enhanced Selectivity in High-Flux Class","volume":"5","author":"Voigt","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1159\/000479264","article-title":"Effects of Hemodialysis Therapy Using Dialyzers with Medium Cut-Off Membranes on Middle Molecules","volume":"191","author":"Kirsch","year":"2017","journal-title":"Contrib. Nephrol."},{"key":"ref_113","doi-asserted-by":"crossref","unstructured":"Zickler, D., Schindler, R., Willy, K., Martus, P., Pawlak, M., Storr, M., Hulko, M., Boehler, T., Glomb, M.A., and Liehr, K. (2017). Medium Cut-Off (MCO) Membranes Reduce Inflammation in Chronic Dialysis Patients-A Randomized Controlled Clinical Trial. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169024"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1681\/ASN.V22122","article-title":"Peritoneal transport physiology: Insights from basic research","volume":"2","author":"Flessner","year":"1991","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2238","DOI":"10.1046\/j.1523-1755.2003.00310.x","article-title":"Removal of middle molecules and protein-bound solutes by peritoneal dialysis and relation with uremic symptoms","volume":"64","author":"Bammens","year":"2003","journal-title":"Kidney Int."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"S292","DOI":"10.1046\/j.1523-1755.2001.59780292.x","article-title":"Uremic toxins and peritoneal dialysis","volume":"78","author":"Lameire","year":"2001","journal-title":"Kidney Int. Suppl."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1681\/ASN.V13suppl_1s84","article-title":"Solute Transport across the Peritoneal Membrane","volume":"13","author":"Leypoldt","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"436","DOI":"10.3747\/pdi.2013.00202","article-title":"Removal of Different Classes of Uremic Toxins in APD vs. CAPD: A Randomized Cross-Over Study","volume":"35","author":"Eloot","year":"2015","journal-title":"Perit. Dial. 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