Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease

Nature Reviews Nephrology volume 17, pages 402–416 (2021)Cite this article

Subjects

Abstract

Chronic kidney disease (CKD) is characterized by the retention of a myriad of solutes termed uraemic (or uremic) toxins, which inflict damage to several organs, including the cardiovascular system. Uraemic toxins can induce hallmarks of cardiovascular disease (CVD), such as atherothrombosis, heart failure, dysrhythmias, vessel calcification and dysregulated angiogenesis. CVD is an important driver of mortality in patients with CKD; however, reliance on conventional approaches to managing CVD risk is insufficient in these patients, underscoring a need to target risk factors that are specific to CKD. Mounting evidence suggests that targeting uraemic toxins and/or pathways induced by uraemic toxins, including tryptophan metabolites and trimethylamine N-oxide (TMAO), can lower the risk of CVD in patients with CKD. Although tangible therapies resulting from our growing knowledge of uraemic toxicity are yet to materialize, a number of pharmacological and non-pharmacological approaches have the potential to abrogate the effects of uraemic toxins, for example, by decreasing the production of uraemic toxins, by modifying metabolic pathways induced by uraemic toxins such as those controlled by aryl hydrocarbon receptor signalling and by augmenting the clearance of uraemic toxins.

Key points

  • Patients with chronic kidney disease (CKD) retain myriad chemical compounds, known as uraemic toxins, that mediate systemic complications including cardiovascular disease (CVD); levels of these toxins rise with CKD progression, further increasing cardiovascular risk.

  • Early interventions that target conventional cardiovascular risk factors, such as obesity and hypertension, combined with approaches to directly target uraemic toxins have potential to lower the risk of CVD in patients with CKD.

  • Non-pharmacological measures to target uraemic toxins include approaches to reduce their biosynthesis through dietary interventions and/or microbial manipulation; both of these approaches have limitations.

  • Pharmacological strategies to suppress cellular events triggered by uraemic toxins are rapidly emerging as an attractive approach and include inhibitors of the aryl hydrocarbon receptor pathway, kinase inhibitors, Klotho or kynureninase supplementation, AST-120, meldonium and 3,3-dimethyl-1-butanol (DMB).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Uraemic toxin production from tryptophan metabolism.
Fig. 2: TMAO synthesis.
Fig. 3: Cardiovascular consequences of uraemic toxicity.
Fig. 4: Consequences of AHR activation.
Fig. 5: Consequences of indoxyl sulfate binding to albumin.

Similar content being viewed by others

References

  1. Hill, N. R. et al. Global prevalence of chronic kidney disease — a systematic review and meta-analysis. PLoS ONE 11, e0158765 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System — United States. CDC https://nccd.cdc.gov/ckd/default.aspx (2021).

  3. Xu, J., Murphy, S. L., Kochanek, K. D. & Bastian, B. A. Deaths: final data for 2013. Natl Vital Stat. Rep. 64, 1–119 (2016).

    PubMed  Google Scholar 

  4. Luyckx, V. A., Tonelli, M. & Stanifer, J. W. The global burden of kidney disease and the sustainable development goals. Bull. World Health Organ. 96, 414–422D (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Centers for Disease Control and Prevention. Chronic kidney disease in the United States, 2019 (CDC, 2019).

  6. Whitman, I. R., Feldman, H. I. & Deo, R. CKD and sudden cardiac death: epidemiology, mechanisms, and therapeutic approaches. J. Am. Soc. Nephrol. 23, 1929–1939 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Charytan, D. M. Introduction: cardiovascular disease in chronic kidney disease. Semin. Nephrol. 38, 541 (2018).

    Article  PubMed  Google Scholar 

  8. Weaver, D. J. & Mitsnefes, M. Cardiovascular disease in children and adolescents with chronic kidney disease. Semin. Nephrol. 38, 559–569 (2018).

    Article  PubMed  Google Scholar 

  9. Temgoua, M. N., Danwang, C., Agbor, V. N. & Noubiap, J. J. Prevalence, incidence and associated mortality of cardiovascular disease in patients with chronic kidney disease in low- and middle-income countries: a protocol for a systematic review and meta-analysis. BMJ Open 7, e016412 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mathew, R. O. et al. Diagnosis and management of atherosclerotic cardiovascular disease in chronic kidney disease: a review. Kidney Int. 91, 797–807 (2017).

    Article  PubMed  Google Scholar 

  11. Chronic Kidney Disease Prognosis Consortium. et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375, 2073–2081 (2010).

    Article  Google Scholar 

  12. van der Velde, M. et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int. 79, 1341–1352 (2011).

    Article  PubMed  CAS  Google Scholar 

  13. Gansevoort, R. T. et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 382, 339–352 (2013).

    Article  PubMed  Google Scholar 

  14. Bansal, N. et al. Absolute rates of heart failure, coronary heart disease, and stroke in chronic kidney disease: an analysis of 3 community-based cohort studies. JAMA Cardiol. 2, 314–318 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Fox, C. S. et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 380, 1662–1673 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Tonelli, M. et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 380, 807–814 (2012).

    Article  PubMed  Google Scholar 

  17. Natsuaki, M. et al. Renal function and effect of statin therapy on cardiovascular outcomes in patients undergoing coronary revascularization (from the CREDO-Kyoto PCI/CABG Registry Cohort-2). Am. J. Cardiol. 110, 1568–1577 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Wanner, C. et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N. Engl. J. Med. 353, 238–248 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Angiolillo, D. J. et al. Impact of chronic kidney disease on platelet function profiles in diabetes mellitus patients with coronary artery disease taking dual antiplatelet therapy. J. Am. Coll. Cardiol. 55, 1139–1146 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Sorensen, V. R., Heaf, J., Wehberg, S. & Sorensen, S. S. Survival benefit in renal transplantation despite high comorbidity. Transplantation 100, 2160–2167 (2016).

    Article  PubMed  Google Scholar 

  21. Rana, A. et al. Survival benefit of solid-organ transplant in the United States. JAMA Surg. 150, 252–259 (2015).

    Article  PubMed  Google Scholar 

  22. Pesavento, T. E. Kidney transplantation in the context of renal replacement therapy. Clin. J. Am. Soc. Nephrol. 4, 2035–2039 (2009).

    Article  PubMed  Google Scholar 

  23. Rao, P. S. et al. Renal transplantation in elderly patients older than 70 years of age: results from the scientific registry of transplant recipients. Transplantation 83, 1069–1074 (2007).

    Article  PubMed  Google Scholar 

  24. Bottomley, M. J. & Harden, P. N. Update on the long-term complications of renal transplantation. Br. Med. Bull. 106, 117–134 (2013).

    Article  CAS  PubMed  Google Scholar 

  25. Gross, M. L. & Ritz, E. Hypertrophy and fibrosis in the cardiomyopathy of uremia–beyond coronary heart disease. Semin. Dial. 21, 308–318 (2008).

    Article  PubMed  Google Scholar 

  26. Price, A. M. et al. Changes in blood pressure and arterial hemodynamics following living kidney donation. Clin. J. Am. Soc. Nephrol. 15, 1330–1339 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ting, S. M. et al. Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation. J. Am. Soc. Nephrol. 25, 187–195 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Poesen, R. et al. The influence of renal transplantation on retained microbial-human co-metabolites. Nephrol. Dial. Transpl. 31, 1721–1729 (2016).

    Article  CAS  Google Scholar 

  29. Liabeuf, S. et al. Levels of indoxyl sulfate in kidney transplant patients, and the relationship with hard outcomes. Circ. J. 80, 722–730 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Liabeuf, S., Cheddani, L. & Massy, Z. A. Uremic toxins and clinical outcomes: the impact of kidney transplantation. Toxins 10, 229 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  31. Masereeuw, R. & Verhaar, M. C. Innovations in approaches to remove uraemic toxins. Nat. Rev. Nephrol. 16, 552–553 (2020).

    Article  PubMed  Google Scholar 

  32. Geremia, I. & Stamatialis, D. Innovations in dialysis membranes for improved kidney replacement therapy. Nat. Rev. Nephrol. 16, 550–551 (2020).

    Article  PubMed  Google Scholar 

  33. Vanholder, R. et al. Uremic toxicity: present state of the art. Int. J. Artif. Organs 24, 695–725 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Duranton, F. et al. Normal and pathologic concentrations of uremic toxins. J. Am. Soc. Nephrol. 23, 1258–1270 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Vanholder, R. C. & Glorieux, G. L. An overview of uremic toxicity. Hemodial. Int. 7, 156–161 (2003).

    Article  PubMed  Google Scholar 

  36. Tang, W. H. et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N. Engl. J. Med. 368, 1575–1584 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Mathew, S. et al. The mechanism of phosphorus as a cardiovascular risk factor in CKD. J. Am. Soc. Nephrol. 19, 1092–1105 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vogt, I., Haffner, D. & Leifheit-Nestler, M. FGF23 and phosphate-cardiovascular toxins in CKD. Toxins 11, 647 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  39. Evenepoel, P., Poesen, R. & Meijers, B. The gut-kidney axis. Pediatr. Nephrol. 32, 2005–2014 (2017).

    Article  PubMed  Google Scholar 

  40. Roager, H. M. & Licht, T. R. Microbial tryptophan catabolites in health and disease. Nat. Commun. 9, 3294 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Kolodziej, L. R., Paleolog, E. M. & Williams, R. O. Kynurenine metabolism in health and disease. Amino Acids 41, 1173–1183 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Saito, K., Crowley, J. S., Markey, S. P. & Heyes, M. P. A mechanism for increased quinolinic acid formation following acute systemic immune stimulation. J. Biol. Chem. 268, 15496–15503 (1993).

    Article  CAS  PubMed  Google Scholar 

  43. Chen, Y. & Guillemin, G. J. Kynurenine pathway metabolites in humans: disease and healthy states. Int. J. Tryptophan Res. 2, 1–19 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Deguchi, T., Kouno, Y., Terasaki, T., Takadate, A. & Otagiri, M. Differential contributions of rOat1 (Slc22a6) and rOat3 (Slc22a8) to the in vivo renal uptake of uremic toxins in rats. Pharm. Res. 22, 619–627 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Uwai, Y., Honjo, H. & Iwamoto, K. Interaction and transport of kynurenic acid via human organic anion transporters hOAT1 and hOAT3. Pharmacol. Res. 65, 254–260 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Saito, K. et al. Mechanism of increases in L-kynurenine and quinolinic acid in renal insufficiency. Am. J. Physiol. Renal Physiol. 279, F565–F572 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Tilg, H. A gut feeling about thrombosis. N. Engl. J. Med. 374, 2494–2496 (2016).

    Article  PubMed  Google Scholar 

  48. Pelletier, C. C. et al. Elevation of trimethylamine-N-oxide in chronic kidney disease: contribution of decreased glomerular filtration rate. Toxins 11, 635 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  49. Block, G. A. et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J. Am. Soc. Nephrol. 15, 2208–2218 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Cheung, A. K. et al. Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study. J. Am. Soc. Nephrol. 17, 546–555 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Liabeuf, S. et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol. Dial. Transpl. 25, 1183–1191 (2010).

    Article  CAS  Google Scholar 

  52. Wu, I. W. et al. Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients — a prospective cohort study. Nephrol. Dial. Transpl. 27, 1169–1175 (2012).

    Article  CAS  Google Scholar 

  53. Stubbs, J. R. et al. Serum trimethylamine-N-oxide is elevated in ckd and correlates with coronary atherosclerosis burden. J. Am. Soc. Nephrol. 27, 305–313 (2016).

    Article  CAS  PubMed  Google Scholar 

  54. Wu, C. C., Hung, S. C., Kuo, K. L. & Tarng, D. C. Impact of indoxyl sulfate on progenitor cell-related neovascularization of peripheral arterial disease and post-angioplasty thrombosis of dialysis vascular access. Toxins 9, 25 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  55. Tomlinson, J. A. P. & Wheeler, D. C. The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease. Kidney Int. 92, 809–815 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Senthong, V. et al. Intestinal microbiota-generated metabolite trimethylamine-N-oxide and 5-year mortality risk in stable coronary artery disease: the contributory role of intestinal microbiota in a COURAGE-like patient cohort. J. Am. Heart Assoc. 5, e002816 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lin, C. J. et al. Indoxyl sulfate predicts cardiovascular disease and renal function deterioration in advanced chronic kidney disease. Arch. Med. Res. 43, 451–456 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Fan, P. C. et al. Serum indoxyl sulfate predicts adverse cardiovascular events in patients with chronic kidney disease. J. Formos. Med. Assoc. 118, 1099–1106 (2019).

    Article  PubMed  Google Scholar 

  59. Meijers, B. K. et al. Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int. 73, 1174–1180 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Pedersen, E. R. et al. Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. Arterioscler. Thromb. Vasc. Biol. 35, 455–462 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Dou, L. et al. The cardiovascular effect of the uremic solute indole-3 acetic acid. J. Am. Soc. Nephrol. 26, 876–887 (2015).

    Article  CAS  PubMed  Google Scholar 

  62. Foley, R. N. et al. Clinical and echocardiographic disease in patients starting end-stage renal disease therapy. Kidney Int. 47, 186–192 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Yang, K. et al. Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway. Toxicol. Lett. 234, 110–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Yisireyili, M. et al. Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats. Life Sci. 92, 1180–1185 (2013).

    Article  CAS  PubMed  Google Scholar 

  65. Han, H. et al. p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J. Am. Heart Assoc. 4, e001852 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Rysz, J., Franczyk, B., Lawinski, J. & Gluba-Brzozka, A. Oxidative stress in ESRD patients on dialysis and the risk of cardiovascular diseases. Antioxidants 9, 1079 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  67. Cybulsky, A. V. Endoplasmic reticulum stress in proteinuric kidney disease. Kidney Int. 77, 187–193 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Dou, L. et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 65, 442–451 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Meijers, B. K. et al. The uremic retention solute p-cresyl sulfate and markers of endothelial damage. Am. J. Kidney Dis. 54, 891–901 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Lin, C. J. et al. Indoxyl sulfate impairs endothelial progenitor cells and might contribute to vascular dysfunction in patients with chronic kidney disease. Kidney Blood Press. Res. 41, 1025–1036 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. De Deyn, P. P., Vanholder, R. & D’Hooge, R. Nitric oxide in uremia: effects of several potentially toxic guanidino compounds. Kidney Int. Suppl. 84, S25–S28 (2003).

    Article  CAS  Google Scholar 

  72. Shivanna, S. et al. The aryl hydrocarbon receptor is a critical regulator of tissue factor stability and an antithrombotic target in uremia. J. Am. Soc. Nephrol. 27, 189–201 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Shashar, M. et al. Targeting STUB1-tissue factor axis normalizes hyperthrombotic uremic phenotype without increasing bleeding risk. Sci. Transl Med. 9, 1–11 (2017).

    Article  CAS  Google Scholar 

  74. Gondouin, B. et al. Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway. Kidney Int. 84, 733–744 (2013).

    Article  CAS  PubMed  Google Scholar 

  75. Karbowska, M. et al. Indoxyl sulfate promotes arterial thrombosis in rat model via increased levels of complex TF/VII, PAI-1, platelet activation as well as decreased contents of SIRT1 and SIRT3. Front. Physiol. 9, 1623 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Chitalia, V. C. et al. Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor. Circulation 127, 365–376 (2013).

    Article  CAS  PubMed  Google Scholar 

  77. Kolachalama, V. B. et al. Uremic solute-aryl hydrocarbon receptor-tissue factor axis associates with thrombosis after vascular injury in humans. J. Am. Soc. Nephrol. 29, 1063–1072 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu, D. et al. Activation of aryl hydrocarbon receptor induces vascular inflammation and promotes atherosclerosis in apolipoprotein E−/− mice. Arterioscler. Thromb. Vasc. Biol. 31, 1260–1267 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Henaut, L., Mary, A., Chillon, J. M., Kamel, S. & Massy, Z. A. The impact of uremic toxins on vascular smooth muscle cell function. Toxins 10, 218 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  80. Yang, K. et al. Indoxyl sulfate induces platelet hyperactivity and contributes to chronic kidney disease-associated thrombosis in mice. Blood 129, 2667–2679 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. Karbowska, M. et al. The uremic toxin indoxyl sulfate accelerates thrombotic response after vascular injury in animal models. Toxins 9, 229 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  82. Wang, X. & Shapiro, J. I. Evolving concepts in the pathogenesis of uraemic cardiomyopathy. Nat. Rev. Nephrol. 15, 159–175 (2019).

    Article  PubMed  Google Scholar 

  83. Eloot, S. et al. Protein-bound uremic toxin profiling as a tool to optimize hemodialysis. PLoS ONE 11, e0147159 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Leong, S. C. & Sirich, T. L. Indoxyl sulfate-review of toxicity and therapeutic strategies. Toxins 8, 358 (2016).

    Article  PubMed Central  CAS  Google Scholar 

  85. Gryp, T., Vanholder, R., Vaneechoutte, M. & Glorieux, G. p-Cresyl Sulfate. Toxins 9, 52 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  86. Barreto, F. C. et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin. J. Am. Soc. Nephrol. 4, 1551–1558 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Debnath, S. et al. Tryptophan metabolism in patients with chronic kidney disease secondary to type 2 diabetes: relationship to inflammatory markers. Int. J. Tryptophan Res. 10, 1178646917694600 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Shivanna, S. et al. The aryl hydrocarbon receptor is a critical regulator of tissue factor stability and an antithrombotic target in uremia. J. Am. Soc. Nephrol. 27, 187–201 (2016).

    Article  Google Scholar 

  89. Vanholder, R. & Glorieux, G. Introduction: uremic toxicity — state of the art 2014. Semin. Nephrol. 34, 85–86 (2014).

    Article  PubMed  Google Scholar 

  90. Vanholder, R., Schepers, E., Pletinck, A., Nagler, E. V. & Glorieux, G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J. Am. Soc. Nephrol. 25, 1897–1907 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Addi, T., Dou, L. & Burtey, S. Tryptophan-derived uremic toxins and thrombosis in chronic kidney disease. Toxins 10, 412 (2018).

    Article  CAS  PubMed Central  Google Scholar 

  92. Konopelski, P. & Ufnal, M. Indoles — gut bacteria metabolites of tryptophan with pharmacotherapeutic potential. Curr. Drug Metab. 19, 883–890 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Mitch, W. E. & Remuzzi, G. Diets for patients with chronic kidney disease, should we reconsider? BMC Nephrol. 17, 80 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Carrero, J. J. et al. Plant-based diets to manage the risks and complications of chronic kidney disease. Nat. Rev. Nephrol. 16, 525–542 (2020).

    Article  PubMed  Google Scholar 

  95. Brunori, G. et al. Efficacy and safety of a very-low-protein diet when postponing dialysis in the elderly: a prospective randomized multicenter controlled study. Am. J. Kidney Dis. 49, 569–580 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Fouque, D., Wang, P., Laville, M. & Boissel, J. P. Low protein diets delay end-stage renal disease in non diabetic adults with chronic renal failure. Cochrane Database Syst. Rev. 2,CD001892 (2000).

    Google Scholar 

  97. Poesen, R. et al. The influence of dietary protein intake on mammalian tryptophan and phenolic metabolites. PLoS ONE 10, e0140820 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Rhee, C. M., Ahmadi, S. F., Kovesdy, C. P. & Kalantar-Zadeh, K. Low-protein diet for conservative management of chronic kidney disease: a systematic review and meta-analysis of controlled trials. J. Cachexia Sarcopenia Muscle 9, 235–245 (2018).

    Article  PubMed  Google Scholar 

  99. Menon, V. et al. Effect of a very low-protein diet on outcomes: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am. J. Kidney Dis. 53, 208–217 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Levey, A. S. et al. Effect of dietary protein restriction on the progression of kidney disease: long-term follow-up of the Modification of Diet in Renal Disease (MDRD) Study. Am. J. Kidney Dis. 48, 879–888 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Li, A., Lee, H. Y. & Lin, Y. C. The effect of ketoanalogues on chronic kidney disease deterioration: a meta-analysis. Nutrients 11, 957 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  102. Kontessis, P. et al. Renal, metabolic and hormonal responses to ingestion of animal and vegetable proteins. Kidney Int. 38, 136–144 (1990).

    Article  CAS  PubMed  Google Scholar 

  103. Azadbakht, L., Atabak, S. & Esmaillzadeh, A. Soy protein intake, cardiorenal indices, and C-reactive protein in type 2 diabetes with nephropathy: a longitudinal randomized clinical trial. Diabetes Care 31, 648–654 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Barcenilla, A. et al. Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl. Env. Microbiol. 66, 1654–1661 (2000).

    Article  CAS  Google Scholar 

  105. Nicholson, J. K. et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Pignanelli, M. et al. Mediterranean diet score: associations with metabolic products of the intestinal microbiome, carotid plaque burden, and renal function. Nutrients 10, 779 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  107. Boutagy, N. E. et al. Short-term high-fat diet increases postprandial trimethylamine-N-oxide in humans. Nutr. Res. 35, 858–864 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Li, T., Chen, Y., Gua, C. & Li, X. Elevated circulating trimethylamine N-oxide levels contribute to endothelial dysfunction in aged rats through vascular inflammation and oxidative stress. Front. Physiol. 8, 350 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Koeth, R. A. et al. gamma-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20, 799–812 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Janeiro, M. H., Ramirez, M. J., Milagro, F. I., Martinez, J. A. & Solas, M. Implication of trimethylamine N-oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients 10, 1398 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  111. Estruch, R. et al. Primary prevention of cardiovascular disease with a Mediterranean diet supplemented with extra-virgin olive oil or nuts. N. Engl. J. Med. 378, e34 (2018).

    Article  CAS  PubMed  Google Scholar 

  112. Wu, Wei-Kai, Chi-Tang Hoc, S. P., Kuod, Ching-Hua, Wub, Ming-Shiang & Shee, Lee-Yan Dietary allicin reduces transformation of L-carnitine to TMAO through impact on gut microbiota. J. Funct. Foods 15, 408–417 (2015).

    Article  CAS  Google Scholar 

  113. Chan, J. Y., Yuen, A. C., Chan, R. Y. & Chan, S. W. A review of the cardiovascular benefits and antioxidant properties of allicin. Phytother. Res. 27, 637–646 (2013).

    Article  CAS  PubMed  Google Scholar 

  114. Shi, X. et al. Allicin improves metabolism in high-fat diet-induced obese mice by modulating the gut microbiota. Nutrients 11, 2909 (2019).

    Article  PubMed Central  Google Scholar 

  115. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chen, K., Zheng, X., Feng, M., Li, D. & Zhang, H. Gut microbiota-dependent metabolite trimethylamine N-oxide contributes to cardiac dysfunction in western diet-induced obese mice. Front. Physiol. 8, 139 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Koeth, R. A. et al. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J. Clin. Invest. 129, 373–387 (2019).

    Article  PubMed  Google Scholar 

  118. Conlon, M. A. & Bird, A. R. The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7, 17–44 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Santisteban, M. M. et al. Hypertension-linked pathophysiological alterations in the gut. Circ. Res. 120, 312–323 (2017).

    Article  CAS  PubMed  Google Scholar 

  120. Jie, Z. et al. The gut microbiome in atherosclerotic cardiovascular disease. Nat. Commun. 8, 845 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Ianiro, G., Tilg, H. & Gasbarrini, A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut 65, 1906–1915 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Andersen, K. et al. Intestinal dysbiosis, barrier dysfunction, and bacterial translocation account for CKD-related systemic inflammation. J. Am. Soc. Nephrol. 28, 76–83 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Wong, J. et al. Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD. Am. J. Nephrol. 39, 230–237 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Goncalves, S. et al. Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol. Dial. Transpl. 21, 2788–2794 (2006).

    Article  CAS  Google Scholar 

  125. Raij, L., Shapiro, F. L. & Michael, A. F. Endotoxemia in febrile reactions during hemodialysis. Kidney Int. 4, 57–60 (1973).

    Article  CAS  PubMed  Google Scholar 

  126. Meijers, B., Evenepoel, P. & Anders, H. J. Intestinal microbiome and fitness in kidney disease. Nat. Rev. Nephrol. 15, 531–545 (2019).

    Article  PubMed  Google Scholar 

  127. Mafra, D. et al. Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nature Rev. Nephrol. 17, 153–171 (2021).

    Article  Google Scholar 

  128. Salmean, Y. A., Segal, M. S., Palii, S. P. & Dahl, W. J. Fiber supplementation lowers plasma p-cresol in chronic kidney disease patients. J. Ren. Nutr. 25, 316–320 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Evenepoel, P., Bammens, B., Verbeke, K. & Vanrenterghem, Y. Acarbose treatment lowers generation and serum concentrations of the protein-bound solute p-cresol: a pilot study. Kidney Int. 70, 192–198 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Mishima, E. et al. Canagliflozin reduces plasma uremic toxins and alters the intestinal microbiota composition in a chronic kidney disease mouse model. Am. J. Physiol. Renal Physiol. 315, F824–F833 (2018).

    Article  CAS  PubMed  Google Scholar 

  131. Marques, F. Z. et al. High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice. Circulation 135, 964–977 (2017).

    Article  CAS  PubMed  Google Scholar 

  132. Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Borges, N. A. et al. Probiotic supplementation in chronic kidney disease: a double-blind, randomized, placebo-controlled trial. J. Ren. Nutr. 28, 28–36 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. Rossi, M. et al. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): a randomized trial. Clin. J. Am. Soc. Nephrol. 11, 223–231 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02302287 (2016).

  136. Din, A. U. et al. Amelioration of TMAO through probiotics and its potential role in atherosclerosis. Appl. Microbiol. Biotechnol. 103, 9217–9228 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Boutagy, N. E. et al. Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity 23, 2357–2363 (2015).

    Article  CAS  PubMed  Google Scholar 

  138. Yacoub, R. & Wyatt, C. M. Manipulating the gut microbiome to decrease uremic toxins. Kidney Int. 91, 521–523 (2017).

    Article  CAS  PubMed  Google Scholar 

  139. Devlin, A. S. et al. Modulation of a circulating uremic solute via rational genetic manipulation of the gut microbiota. Cell Host Microbe 20, 709–715 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Roberts, A. B. et al. Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat. Med. 24, 1407–1417 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Colosimo, D. A. et al. Mapping interactions of microbial metabolites with human G-protein-coupled receptors. Cell Host Microbe 26, 273–282.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Dethlefsen, L., McFall-Ngai, M. & Relman, D. A. An ecological and evolutionary perspective on human-microbe mutualism and disease. Nature 449, 811–818 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Gryp, T. et al. Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease. Kidney Int. 97, 1230–1242 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Ascenzi, P. & Fasano, M. Allostery in a monomeric protein: the case of human serum albumin. Biophys. Chem. 148, 16–22 (2010).

    Article  CAS  PubMed  Google Scholar 

  145. Sarnatskaya, V. V. et al. Effect of protein-bound uraemic toxins on the thermodynamic characteristics of human albumin. Biochem. Pharmacol. 63, 1287–1296 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Meijers, B. K., Bammens, B., Verbeke, K. & Evenepoel, P. A review of albumin binding in CKD. Am. J. Kidney Dis. 51, 839–850 (2008).

    Article  PubMed  Google Scholar 

  147. Zaidi, N., Ajmal, M. R., Rabbani, G., Ahmad, E. & Khan, R. H. A comprehensive insight into binding of hippuric acid to human serum albumin: a study to uncover its impaired elimination through hemodialysis. PLoS ONE 8, e71422 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Ghuman, J. et al. Structural basis of the drug-binding specificity of human serum albumin. J. Mol. Biol. 353, 38–52 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Meyer, T. W. The removal of protein-bound solutes by dialysis. J. Ren. Nutr. 22, 203–206 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Krieter, D. H. et al. Protein-bound uraemic toxin removal in haemodialysis and post-dilution haemodiafiltration. Nephrol. Dial. Transpl. 25, 212–218 (2010).

    Article  CAS  Google Scholar 

  151. Niwa, T. Removal of protein-bound uraemic toxins by haemodialysis. Blood Purif. 35, 20–25 (2013).

    Article  CAS  PubMed  Google Scholar 

  152. Meijers, B. K. et al. Major coagulation disturbances during fractionated plasma separation and adsorption. Am. J. Transpl. 7, 2195–2199 (2007).

    Article  CAS  Google Scholar 

  153. Tao, X. et al. Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: an in vitro human whole blood study. Sci. Rep. 6, 23389 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Sakaguchi, Y. et al. A randomized trial of magnesium oxide and oral carbon adsorbent for coronary artery calcification in predialysis CKD. J. Am. Soc. Nephrol. 30, 1073–1085 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kuro, O. M. The Klotho proteins in health and disease. Nat. Rev. Nephrol. 15, 27–44 (2019).

    Article  CAS  Google Scholar 

  156. Chen, J., Fan, J., Wang, S. & Sun, Z. Secreted klotho attenuates inflammation-associated aortic valve fibrosis in senescence-accelerated mice P1. Hypertension 71, 877–885 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Sahu, A. et al. Age-related declines in alpha-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nat. Commun. 9, 4859 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Fan, J. & Sun, Z. The antiaging gene Klotho regulates proliferation and differentiation of adipose-derived stem cells. Stem Cell 34, 1615–1625 (2016).

    Article  CAS  Google Scholar 

  159. Hu, M. C. et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J. Am. Soc. Nephrol. 22, 124–136 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Rotondi, S. et al. Soluble alpha-klotho serum levels in chronic kidney disease. Int. J. Endocrinol. 2015, 872193 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Sun, C. Y., Chang, S. C. & Wu, M. S. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int. 81, 640–650 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hu, M. C. et al. Recombinant alpha-Klotho may be prophylactic and therapeutic for acute to chronic kidney disease progression and uremic cardiomyopathy. Kidney Int. 91, 1104–1114 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Yang, K. et al. Klotho protects against indoxyl sulphate-induced myocardial hypertrophy. J. Am. Soc. Nephrol. 26, 2434–2446 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kitagawa, M. et al. A decreased level of serum soluble Klotho is an independent biomarker associated with arterial stiffness in patients with chronic kidney disease. PLoS ONE 8, e56695 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Seiler, S. et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2–4. Clin. J. Am. Soc. Nephrol. 9, 1049–1058 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03996746 (2020).

  167. Lund, A. K., Goens, M. B., Nunez, B. A. & Walker, M. K. Characterizing the role of endothelin-1 in the progression of cardiac hypertrophy in aryl hydrocarbon receptor (AhR) null mice. Toxicol. Appl. Pharmacol. 212, 127–135 (2006).

    Article  CAS  PubMed  Google Scholar 

  168. Sauzeau, V. et al. Transcriptional factor aryl hydrocarbon receptor (Ahr) controls cardiovascular and respiratory functions by regulating the expression of the Vav3 proto-oncogene. J. Biol. Chem. 286, 2896–2909 (2011).

    Article  CAS  PubMed  Google Scholar 

  169. Juan, S. H., Lee, J. L., Ho, P. Y., Lee, Y. H. & Lee, W. S. Antiproliferative and antiangiogenic effects of 3-methylcholanthrene, an aryl-hydrocarbon receptor agonist, in human umbilical vascular endothelial cells. Eur. J. Pharmacol. 530, 1–8 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Ichihara, S. et al. A role for the aryl hydrocarbon receptor in regulation of ischemia-induced angiogenesis. Arterioscler. Thromb. Vasc. Biol. 27, 1297–1304 (2007).

    Article  CAS  PubMed  Google Scholar 

  171. Vasquez, A. et al. A role for the aryl hydrocarbon receptor in cardiac physiology and function as demonstrated by AhR knockout mice. Cardiovasc. Toxicol. 3, 153–163 (2003).

    Article  CAS  PubMed  Google Scholar 

  172. Agbor, L. N., Elased, K. M. & Walker, M. K. Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness. Biochem. Pharmacol. 82, 514–523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Xue, Y. et al. Baicalin inhibits inflammation and attenuates myocardial ischaemic injury by aryl hydrocarbon receptor. J. Pharm. Pharmacol. 67, 1756–1764 (2015).

    Article  CAS  PubMed  Google Scholar 

  174. Schroeder, J. C. et al. The uremic toxin 3-indoxyl sulfate is a potent endogenous agonist for the human aryl hydrocarbon receptor. Biochemistry 49, 393–400 (2010).

    Article  CAS  PubMed  Google Scholar 

  175. Dou, L. et al. Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease. Kidney Int. 93, 986–999 (2018).

    Article  CAS  PubMed  Google Scholar 

  176. Walker, J. A. et al. Temporal and tissue-specific activation of aryl hydrocarbon receptor in discrete mouse models of kidney disease. Kidney Int. 97, 538–550 (2020).

    Article  CAS  PubMed  Google Scholar 

  177. McDonough, H. & Patterson, C. CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8, 303–308 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Hiyoshi, H. et al. 2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP. Sci. Rep. 4, 7095 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Fox, K. A. et al. The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J. Am. Coll. Cardiol. 49, 2249–2255 (2007).

    Article  CAS  PubMed  Google Scholar 

  180. Flaveny, C. A. & Perdew, G. H. Transgenic humanized AHR mouse reveals differences between human and mouse AHR ligand selectivity. Mol. Cell Pharmacol. 1, 119–123 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Flaveny, C. A., Murray, I. A. & Perdew, G. H. Differential gene regulation by the human and mouse aryl hydrocarbon receptor. Toxicol. Sci. 114, 217–225 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Chang, X. et al. Ligand-independent regulation of transforming growth factor beta1 expression and cell cycle progression by the aryl hydrocarbon receptor. Mol. Cell Biol. 27, 6127–6139 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Bunger, M. K. et al. Abnormal liver development and resistance to 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in mice carrying a mutation in the DNA-binding domain of the aryl hydrocarbon receptor. Toxicol. Sci. 106, 83–92 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Lindsey, S., Jiang, J., Woulfe, D. & Papoutsakis, E. T. Platelets from mice lacking the aryl hydrocarbon receptor exhibit defective collagen-dependent signaling. J. Thromb. Haemost. 12, 383–394 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Fujii-Kuriyama, Y. & Mimura, J. Molecular mechanisms of AhR functions in the regulation of cytochrome P450 genes. Biochem. Biophys. Res. Commun. 338, 311–317 (2005).

    Article  CAS  PubMed  Google Scholar 

  186. Santana Machado, T., Cerini, C. & Burtey, S. Emerging roles of aryl hydrocarbon receptors in the altered clearance of drugs during chronic kidney disease. Toxins 11, 209 (2019).

    Article  PubMed Central  Google Scholar 

  187. Santana Machado, T. et al. Indoxyl sulfate upregulates liver P-glycoprotein expression and activity through aryl hydrocarbon receptor signaling. J. Am. Soc. Nephrol. 29, 906–918 (2018).

    Article  PubMed  Google Scholar 

  188. Hankinson, O. The role of AHR-inducible cytochrome P450s in metabolism of polyunsaturated fatty acids. Drug Metab. Rev. 48, 342–350 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Schmees, N. et al. Identification of BAY-218, a potent and selective small-molecule AhR inhibitor, as a new modality to counteract tumor immunosuppression [abstract 4454]. Cancer Res. 79 (Suppl. 13), 4454 (2019).

    Article  Google Scholar 

  190. Parks, A. J. et al. In silico identification of an aryl hydrocarbon receptor antagonist with biological activity in vitro and in vivo. Mol. Pharmacol. 86, 593–608 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Lin, A. et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci. Transl Med. 11, eaaw8412 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Smith, K. J. et al. Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J. Pharmacol. Exp. Ther. 338, 318–327 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Murray, I. A. et al. Evidence for ligand-mediated selective modulation of aryl hydrocarbon receptor activity. Mol. Pharmacol. 77, 247–254 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Murray, I. A. et al. Suppression of cytokine-mediated complement factor gene expression through selective activation of the Ah receptor with 3′,4′-dimethoxy-alpha-naphthoflavone. Mol. Pharmacol. 79, 508–519 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Murray, I. A. et al. Antagonism of aryl hydrocarbon receptor signaling by 6,2′,4′-trimethoxyflavone. J. Pharmacol. Exp. Ther. 332, 135–144 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04069026 (2021).

  197. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04200963 (2020).

  198. Zuo, H. et al. Plasma biomarkers of inflammation, the kynurenine pathway, and risks of all-cause, cancer, and cardiovascular disease mortality: the hordaland health study. Am. J. Epidemiol. 183, 249–258 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  199. Prendergast, G. C., Malachowski, W. P., DuHadaway, J. B. & Muller, A. J. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 77, 6795–6811 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Triplett, T. A. et al. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36, 758–764 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Lugo-Huitron, R. et al. Quinolinic acid: an endogenous neurotoxin with multiple targets. Oxid. Med. Cell. Longev. 2013, 104024 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Bugnicourt, J. M., Godefroy, O., Chillon, J. M., Choukroun, G. & Massy, Z. A. Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J. Am. Soc. Nephrol. 24, 353–363 (2013).

    Article  CAS  PubMed  Google Scholar 

  203. Wang, J. & Zhuang, S. Src family kinases in chronic kidney disease. Am. J. Physiol. Renal Physiol 313, F721–F728 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Lan, A. & Du, J. Potential role of Akt signaling in chronic kidney disease. Nephrol. Dial. Transpl. 30, 385–394 (2015).

    Article  CAS  Google Scholar 

  205. Shahin, R., Shaheen, O., El-Dahiyat, F., Habash, M. & Saffour, S. Research advances in kinase enzymes and inhibitors for cardiovascular disease treatment. Future Sci. OA 3, FSO204 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Ryu, J. H. & Kim, S. J. Clopidogrel effectively suppresses endothelial microparticle generation induced by indoxyl sulfate via inhibition of the p38 mitogen-activated protein kinase pathway. Blood Purif. 32, 186–194 (2011).

    Article  CAS  PubMed  Google Scholar 

  207. Owens, A. P. 3rd. & Mackman, N. Microparticles in hemostasis and thrombosis. Circ. Res. 108, 1284–1297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Wu, P., Nielsen, T. E. & Clausen, M. H. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol. Sci. 36, 422–439 (2015).

    Article  CAS  PubMed  Google Scholar 

  209. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat. Med. 19, 576–585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Kuka, J. et al. The cardioprotective effect of mildronate is diminished after co-treatment with L-carnitine. J. Cardiovasc. Pharmacol. Ther. 17, 215–222 (2012).

    Article  CAS  PubMed  Google Scholar 

  211. Kuka, J. et al. Suppression of intestinal microbiota-dependent production of pro-atherogenic trimethylamine N-oxide by shifting L-carnitine microbial degradation. Life Sci. 117, 84–92 (2014).

    Article  CAS  PubMed  Google Scholar 

  212. Konop, M. et al. Enalapril decreases rat plasma concentration of TMAO, a gut bacteria-derived cardiovascular marker. Biomarkers 23, 380–385 (2018).

    Article  CAS  PubMed  Google Scholar 

  213. Sato, E. et al. Impact of the oral adsorbent AST-120 on organ-specific accumulation of uremic toxins: LC-MS/MS and MS imaging techniques. Toxins 10, 19 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  214. Liu, W. C., Tomino, Y. & Lu, K. C. Impacts of indoxyl sulfate and p-cresol sulfate on chronic kidney disease and mitigating effects of AST-120. Toxins 10, 367 (2018).

    Article  PubMed Central  CAS  Google Scholar 

  215. Asai, M., Kumakura, S. & Kikuchi, M. Review of the efficacy of AST-120 (KREMEZIN®) on renal function in chronic kidney disease patients. Ren. Fail. 41, 47–56 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Yamaguchi, J., Tanaka, T. & Inagi, R. Effect of AST-120 in chronic kidney disease treatment: still a controversy? Nephron 135, 201–206 (2017).

    Article  CAS  PubMed  Google Scholar 

  217. Schulman, G. et al. Randomized placebo-controlled EPPIC trials of AST-120 in CKD. J. Am. Soc. Nephrol. 26, 1732–1746 (2015).

    Article  CAS  PubMed  Google Scholar 

  218. Goto, S. et al. Association between AST-120 and abdominal aortic calcification in predialysis patients with chronic kidney disease. Clin. Exp. Nephrol. 17, 365–371 (2013).

    Article  CAS  PubMed  Google Scholar 

  219. Eknoyan, G. et al. Effect of dialysis dose and membrane flux in maintenance hemodialysis. N. Engl. J. Med. 347, 2010–2019 (2002).

    Article  PubMed  Google Scholar 

  220. Wieringa, F. P. & Kooman, J. P. Smart sensors for real-time monitoring of patients on dialysis. Nat. Rev. Nephrol. 16, 554–555 (2020).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by NIH grants R01 HL132325 and R21 DK119740-01 to V.C.C. We thank the Evans Center for Interdisciplinary Biomedical Research and the Department of Medicine at Boston University School of Medicine for their ongoing support of Affinity Research Collaboratives on Thrombosis and Hemostasis.

Author information

Authors and Affiliations

  1. School of Medicine, Boston University School of Medicine, Boston, MA, USA

    Jonathan D. Ravid

  2. Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Mohamed Hassan Kamel & Vipul C. Chitalia

  3. Boston Veterans Affairs Healthcare System, Boston, MA, USA

    Vipul C. Chitalia

  4. Global Co-creation Lab, Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA

    Vipul C. Chitalia

Authors
  1. Jonathan D. Ravid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamed Hassan Kamel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vipul C. Chitalia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to writing and reviewing/editing before submission.

Corresponding author

Correspondence to Vipul C. Chitalia.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks P. Evenepoel, J. Shapiro and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Phase I metabolism

Biochemical processing of the parent drug (by oxidation, reduction or hydrolysis) to convert it into a more polar molecule.

Phase II metabolism

A phase of drug metabolism that involves conjugation of the drug by coupling it or its metabolites to another molecule to augment its excretion.

Transamination

A biochemical process whereby an amino group from an amino acid is exchanged for a keto acid, generating an amino acid version of the keto acid and a keto acid version of the original amino acid.

Cruciferae

A large family of plants with four-petalled flowers that includes cabbage, brussels sprouts, broccoli and turnips.

Prebiotics

Components of food that induce the growth or activity of beneficial microorganisms to maintain microbial homeostasis.

Probiotics

Live microorganisms that can improve or restore the gut flora to maintain microbial homeostasis.

Synbiotics

A combination of probiotics and prebiotics that are intended to improve the survival and activity of beneficial microorganisms in the gut.

Xenobiotic

A chemical substance found within an organism that is not naturally produced or expected to be present within the organism or in an ecological system.

Aza-analogue

Chemical compounds in which a carbon atom is replaced by a nitrogen atom.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ravid, J.D., Kamel, M.H. & Chitalia, V.C. Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease. Nat Rev Nephrol 17, 402–416 (2021). https://doi.org/10.1038/s41581-021-00408-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-021-00408-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing