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An update on uremic toxins

  • Nephrology - Review
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Abstract

In the last decade, uremic toxicity as a potential cause for the excess of cardiovascular disease and mortality observed in chronic kidney disease gained more and more interest. This review focuses on uremic toxins with known cardiovascular effects and their removal. For protein-bound solutes, for example, indoxylsulfate and the conjugates of p-cresol, and for small water-soluble solutes, for example, guanidines, such as ADMA and SDMA, there is a growing evidence for a role in cardiovascular toxicity in vitro (e.g., affecting leukocyte, endothelial, vascular smooth muscle cell function) and/or in vivo. Several middle molecules (e.g., beta-2-microglobulin, interleukin-6, TNF-alpha and FGF-23) were shown to be predictors for cardiovascular disease and/or mortality. Most of these solutes, however, are difficult to remove during dialysis, which is traditionally assessed by studying the removal of urea, which can be considered as a relatively inert uremic retention solute. However, even the effective removal of other small water-soluble toxins than urea can be hampered by their larger distribution volumes. Middle molecules (beta-2-microglobulin as prototype, but not necessarily representative for others) are cleared more efficiently when the pore size of the dialyzer membrane increases, convection is applied and dialysis time is prolonged. Only adding convection to diffusion improves the removal of protein-bound toxins. Therefore, alternative removal strategies, such as intestinal adsorption, drugs interfering with toxic biochemical pathways or decreasing toxin concentration, and extracorporeal plasma adsorption, as well as kinetic behavior during dialysis need further investigation. Even more importantly, randomized clinical studies are required to demonstrate a survival advantage through these strategies.

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References

  1. Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N (2005) Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transpl 20:1048–1056

    Article  CAS  Google Scholar 

  2. Vanholder R, De Smet R, Glorieux G et al (2003) Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 63:1934–1943

    Article  PubMed  CAS  Google Scholar 

  3. Duranton F, Cohen G, De Smet R et al (2012) Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol 23:1258–1270

    Google Scholar 

  4. Johnson WJ, Hagge WW, Wagoner RD, Dinapoli RP, Rosevear JW (1972) Effects of urea loading in patients with far-advanced renal failure. Mayo Clin Proc 47:21–29

    PubMed  CAS  Google Scholar 

  5. Eknoyan G, Beck GJ, Cheung AK et al (2002) Effect of dialysis dose and membrane flux in maintenance hemodialysis. N Engl J Med 347:2010–2019

    Article  PubMed  Google Scholar 

  6. Paniagua R, Amato D, Vonesh E et al (2002) Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. J Am Soc Nephrol 13:1307–1320

    PubMed  CAS  Google Scholar 

  7. Owen WF Jr, Lew NL, Liu Y, Lowrie EG, Lazarus JM (1993) The urea reduction ratio and serum albumin concentration as predictors of mortality in patients undergoing hemodialysis. N Engl J Med 329:1001–1006

    Article  PubMed  Google Scholar 

  8. Lindner A, Charra B, Sherrard DJ, Scribner BH (1974) Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 290:697–701

    Article  PubMed  CAS  Google Scholar 

  9. Santoro A, Mancini E, Bolzani R et al (2008) The effect of on-line high-flux hemofiltration versus low-flux hemodialysis on mortality in chronic kidney failure: a small randomized controlled trial. Am J Kidney Dis 52:507–518

    Article  PubMed  CAS  Google Scholar 

  10. Locatelli F, Martin-Malo A, Hannedouche T et al (2009) Effect of membrane permeability on survival of hemodialysis patients. J Am Soc Nephrol 20:645–654

    Article  PubMed  Google Scholar 

  11. D’Apolito M, Du X, Zong H et al (2010) Urea-induced ROS generation causes insulin resistance in mice with chronic renal failure. J Clin Invest 120:203–213

    Article  PubMed  Google Scholar 

  12. D’Hooge R, Van de Vijver G, Van Bogaert PP, Marescau B, Vanholder R, De Deyn PP (2003) Involvement of voltage- and ligand-gated Ca2+ channels in the neuroexcitatory and synergistic effects of putative uremic neurotoxins. Kidney Int 63:1764–1775

    Article  PubMed  Google Scholar 

  13. D’Hooge R, Pei YQ, Marescau B, De Deyn PP (1992) Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice. J Neurol Sci 112:96–105

    Article  PubMed  Google Scholar 

  14. Schepers E, Glorieux G, Dou L et al (2010) Guanidino compounds as cause of cardiovascular damage in chronic kidney disease: an in vitro evaluation. Blood Purif 30:277–287

    Article  PubMed  CAS  Google Scholar 

  15. Glorieux GL, Dhondt AW, Jacobs P et al (2004) In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection. Kidney Int 65:2184–2192

    Article  PubMed  CAS  Google Scholar 

  16. Schepers E, Barreto DV, Liabeuf S et al (2011) Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. Clin J Am Soc Nephrol 6:2374–2383

    Article  PubMed  CAS  Google Scholar 

  17. Eloot S, Van Biesen W, Dhondt A et al (2008) Impact of hemodialysis duration on the removal of uremic retention solutes. Kidney Int 73:765–770

    Article  PubMed  CAS  Google Scholar 

  18. Eloot S, Torremans A, De Smet R et al (2007) Complex compartmental behavior of small water-soluble uremic retention solutes: evaluation by direct measurements in plasma and erythrocytes. Am J Kidney Dis 50:279–288

    Article  PubMed  CAS  Google Scholar 

  19. Eloot S, Van Biesen W, Dhondt A et al (2009) Impact of increasing haemodialysis frequency versus haemodialysis duration on removal of urea and guanidino compounds: a kinetic analysis. Nephrol Dial Transpl 24:2225–2232

    Article  CAS  Google Scholar 

  20. Zhao D, Sonawane ND, Levin MH, Yang B (2007) Comparative transport efficiencies of urea analogues through urea transporter UT-B. Biochim Biophys Acta 1768:1815–1821

    Article  PubMed  CAS  Google Scholar 

  21. Cheung AK, Alford MF, Wilson MM, Leypoldt JK, Henderson LW (1983) Urea movement across erythrocyte membrane during artificial kidney treatment. Kidney Int 23:866–869

    Article  PubMed  CAS  Google Scholar 

  22. Leiper J, Vallance P (1999) Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 43:542–548

    Article  PubMed  CAS  Google Scholar 

  23. Meinitzer A, Seelhorst U, Wellnitz B et al (2007) Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study). Clin Chem 53:273–283

    Article  PubMed  CAS  Google Scholar 

  24. Zoccali C, Bode-Boger S, Mallamaci F et al (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358:2113–2117

    Article  PubMed  CAS  Google Scholar 

  25. Zoccali C, Benedetto FA, Maas R et al (2002) Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol 13:490–496

    Article  PubMed  CAS  Google Scholar 

  26. Kielstein JT, Impraim B, Simmel S et al (2004) Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 109:172–177

    Article  PubMed  CAS  Google Scholar 

  27. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575

    Article  PubMed  CAS  Google Scholar 

  28. Bode-Boger SM, Scalera F, Kielstein JT et al (2006) Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J Am Soc Nephrol 17:1128–1134

    Article  PubMed  CAS  Google Scholar 

  29. Schepers E, Glorieux G, Dhondt A, Leybaert L, Vanholder R (2009) Role of symmetric dimethylarginine in vascular damage by increasing ROS via store-operated calcium influx in monocytes. Nephrol Dial Transpl 24:1429–1435

    Article  CAS  Google Scholar 

  30. Kielstein JT, Boger RH, Bode-Boger SM et al (2004) Low dialysance of asymmetric dimethylarginine (ADMA)—in vivo and in vitro evidence of significant protein binding. Clin Nephrol 62:295–300

    PubMed  CAS  Google Scholar 

  31. Boger RH (2004) Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “l-arginine paradox” and acts as a novel cardiovascular risk factor. J Nutr 134:2842S–2847S

    PubMed  Google Scholar 

  32. Tanaka M, Sydow K, Gunawan F et al (2005) Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease. Circulation 112:1549–1556

    Article  PubMed  CAS  Google Scholar 

  33. Jacobi J, Maas R, Cordasic N et al (2008) Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice. Am J Physiol Heart Circ Physiol 294:H1058–H1066

    Article  PubMed  CAS  Google Scholar 

  34. Leiper J, Nandi M, Torondel B et al (2007) Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med 13:198–203

    Article  PubMed  CAS  Google Scholar 

  35. Koyama K, Ito A, Yamamoto J et al (2010) Randomized controlled trial of the effect of short-term coadministration of methylcobalamin and folate on serum ADMA concentration in patients receiving long-term hemodialysis. Am J Kidney Dis 55:1069–1078

    Article  PubMed  CAS  Google Scholar 

  36. Vanholder R, Van Laecke S, Glorieux G (2008) The middle-molecule hypothesis 30 years after: lost and rediscovered. J Nephrol 21:146–160

    PubMed  CAS  Google Scholar 

  37. Wilson AM, Kimura E, Harada RK et al (2007) Beta2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation 116:1396–1403

    Article  PubMed  CAS  Google Scholar 

  38. Saijo Y, Utsugi M, Yoshioka E et al (2005) Relationship of beta2-microglobulin to arterial stiffness in Japanese subjects. Hypertens Res 28:505–511

    Article  PubMed  CAS  Google Scholar 

  39. Ripoll E, Revilla M, Hernandez ER, Arribas I, Villa LF, Rico H (1996) New evidence that serum beta(2)-microglobulin behaves as a biological marker of bone remodelling in women. Eur J Clin Invest 26:681–685

    Article  PubMed  CAS  Google Scholar 

  40. Cheung AK, Rocco MV, Yan G et al (2006) Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study. J Am Soc Nephrol 17:546–555

    Article  PubMed  CAS  Google Scholar 

  41. Cheung AK, Greene T, Leypoldt JK et al (2008) Association between serum 2-microglobulin level and infectious mortality in hemodialysis patients. Clin J Am Soc Nephrol 3:69–77

    Article  PubMed  CAS  Google Scholar 

  42. Barreto DV, Barreto FC, Liabeuf S et al (2010) Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease. Kidney Int 77:550–556

    Article  PubMed  CAS  Google Scholar 

  43. Kimmel PL, Phillips TM, Simmens SJ et al (1998) Immunologic function and survival in hemodialysis patients. Kidney Int 54:236–244

    Article  PubMed  CAS  Google Scholar 

  44. Fliser D, Kollerits B, Neyer U et al (2007) Fibroblast growth factor 23 (FGF23) predicts progression of chronic kidney disease: the Mild to Moderate Kidney Disease (MMKD) Study. J Am Soc Nephrol 18:2600–2608

    Article  PubMed  CAS  Google Scholar 

  45. Seiler S, Cremers B, Rebling NM et al (2011) The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur Heart J 32:2688–2696

    Article  PubMed  CAS  Google Scholar 

  46. Gutierrez OM, Januzzi JL, Isakova T et al (2009) Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119:2545–2552

    Article  PubMed  CAS  Google Scholar 

  47. Gutierrez OM, Mannstadt M, Isakova T et al (2008) Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 359:584–592

    Article  PubMed  CAS  Google Scholar 

  48. Faul C, Amaral AP, Oskouei B et al (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121:4393–4408

    Article  PubMed  CAS  Google Scholar 

  49. Maduell F, Navarro V, Cruz MC et al (2002) Osteocalcin and myoglobin removal in on-line hemodiafiltration versus low- and high-flux hemodialysis. Am J Kidney Dis 40:582–589

    Article  PubMed  CAS  Google Scholar 

  50. Locatelli F, Mastrangelo F, Redaelli B et al (1996) Effects of different membranes and dialysis technologies on patient treatment tolerance and nutritional parameters. The Italian Cooperative Dialysis Study Group. Kidney Int 50:1293–1302

    Article  PubMed  CAS  Google Scholar 

  51. Meert N, Eloot S, Waterloos MA et al (2009) Effective removal of protein-bound uraemic solutes by different convective strategies: a prospective trial. Nephrol Dial Transpl 24:562–570

    Article  CAS  Google Scholar 

  52. Meert N, Beerenhout C, Schepers E, Glorieux G, Kooman J, Vanholder R (2009) Evolution of protein-bound uraemic solutes during predilution haemofiltration. J Nephrol 22:352–357

    PubMed  CAS  Google Scholar 

  53. Meert N, Waterloos MA, Van Landschoot M et al (2010) Prospective evaluation of the change of predialysis protein-bound uremic solute concentration with postdilution online hemodiafiltration. Artif Organs 34:580–585

    Article  PubMed  CAS  Google Scholar 

  54. Meert N, Eloot S, Schepers E et al (2011) Comparison of removal capacity of two consecutive generations of high-flux dialysers during different treatment modalities. Nephrol Dial Transpl 26:2624–2630

    Article  Google Scholar 

  55. Ward RA, Schmidt B, Hullin J, Hillebrand GF, Samtleben W (2000) A comparison of on-line hemodiafiltration and high-flux hemodialysis: a prospective clinical study. J Am Soc Nephrol 11:2344–2350

    PubMed  CAS  Google Scholar 

  56. Leypoldt JK, Cheung AK, Deeter RB (1999) Rebound kinetics of beta2-microglobulin after hemodialysis. Kidney Int 56:1571–1577

    Article  PubMed  CAS  Google Scholar 

  57. Stiller S, Xu XQ, Gruner N, Vienken J, Mann H (2002) Validation of a two-pool model for the kinetics of beta2-microglobulin. Int J Artif Organs 25:411–420

    PubMed  CAS  Google Scholar 

  58. Odell RA, Slowiaczek P, Moran JE, Schindhelm K (1991) Beta 2-microglobulin kinetics in end-stage renal failure. Kidney Int 39:909–919

    Article  PubMed  CAS  Google Scholar 

  59. Basile C, Libutti P, Di Turo AL et al (2011) Removal of uraemic retention solutes in standard bicarbonate haemodialysis and long-hour slow-flow bicarbonate haemodialysis. Nephrol Dial Transpl 26:1296–1303

    Article  CAS  Google Scholar 

  60. Cheung AK, Levin NW, Greene T et al (2003) Effects of high-flux hemodialysis on clinical outcomes: results of the HEMO study. J Am Soc Nephrol 14:3251–3263

    Article  PubMed  Google Scholar 

  61. Delmez JA, Yan G, Bailey J et al (2006) Cerebrovascular disease in maintenance hemodialysis patients: results of the HEMO Study. Am J Kidney Dis 47:131–138

    Article  PubMed  Google Scholar 

  62. Krane V, Krieter DH, Olschewski M et al (2007) Dialyzer membrane characteristics and outcome of patients with type 2 diabetes on maintenance hemodialysis. Am J Kidney Dis 49:267–275

    Article  PubMed  CAS  Google Scholar 

  63. Chauveau P, Nguyen H, Combe C et al (2005) Dialyzer membrane permeability and survival in hemodialysis patients. Am J Kidney Dis 45:565–571

    Article  PubMed  Google Scholar 

  64. Locatelli F, Hannedouche T, Jacobson S et al (1999) The effect of membrane permeability on ESRD: design of a prospective randomised multicentre trial. J Nephrol 12:85–88

    PubMed  CAS  Google Scholar 

  65. Lopes AA, Elder SJ, Ginsberg N et al (2007) Lack of appetite in haemodialysis patients–associations with patient characteristics, indicators of nutritional status and outcomes in the international DOPPS. Nephrol Dial Transpl 22:3538–3546

    Article  Google Scholar 

  66. Locatelli F, Altieri P, Andrulli S et al (2010) Hemofiltration and hemodiafiltration reduce intradialytic hypotension in ESRD. J Am Soc Nephrol 21:1798–1807

    Article  PubMed  CAS  Google Scholar 

  67. Ok E, Asci G, Ok ES et al (2011) Comparison of postdilution on-line hemodiafiltration and hemodialysis (Turkish HDF study). In: 48th ERA-EDTA Congress Prague—Abstract LBCT2

  68. Grooteman MP, van den Dorpel MA, Bots ML et al (2012) Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes. J Am Soc Nephrol 23:1087–1096

    Google Scholar 

  69. Jourde-Chiche N, Dou L, Cerini C, Gnat-George F, Vanholder R, Brunet P (2009) Protein-bound toxins—update 2009. Semin Dial 22:334–339

    Article  PubMed  Google Scholar 

  70. Vanholder R, Bammens B, de Loor H et al (2011) Warning: the unfortunate end of p-cresol as a uraemic toxin. Nephrol Dial Transpl 26:1464–1467

    Article  CAS  Google Scholar 

  71. Martinez AW, Recht NS, Hostetter TH, Meyer TW (2005) Removal of P-cresol sulfate by hemodialysis. J Am Soc Nephrol 16:3430–3436

    Article  PubMed  CAS  Google Scholar 

  72. de Loor H, Bammens B, Evenepoel P, De Preter V, Verbeke K (2005) Gas chromatographic-mass spectrometric analysis for measurement of p-cresol and its conjugated metabolites in uremic and normal serum. Clin Chem 51:1535–1538

    Article  PubMed  CAS  Google Scholar 

  73. Vanholder R, De Smet R, Waterloos MA et al (1995) Mechanisms of uremic inhibition of phagocyte reactive species production: characterization of the role of p-cresol. Kidney Int 47:510–517

    Article  PubMed  CAS  Google Scholar 

  74. Schepers E, Meert N, Glorieux G, Goeman J, Van der EJ, Vanholder R (2007) P-cresylsulphate, the main in vivo metabolite of p-cresol, activates leucocyte free radical production. Nephrol Dial Transpl 22:592–596

    Article  CAS  Google Scholar 

  75. Meert N, Schepers E, Glorieux G et al (2011) Novel method for simultaneous determination of p-cresylsulphate and p-cresylglucuronide: clinical data and pathophysiological implications. Nephrol Dial Transpl 27:2388–2396

    Google Scholar 

  76. Meijers BK, Van KS, Verbeke K et al (2009) The uremic retention solute p-cresyl sulfate and markers of endothelial damage. Am J Kidney Dis 54:891–901

    Article  PubMed  CAS  Google Scholar 

  77. Sun CY, Chang SC, Wu MS (2012) Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-to-mesenchymal transition. PLoS One 7:e34026

    Article  PubMed  CAS  Google Scholar 

  78. Sun CY, Chang SC, Wu MS (2012) Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int 81:640–650

    Article  PubMed  CAS  Google Scholar 

  79. Pletinck A, Glorieux G, Schepers E et al (2012) In vivo effects of the protein-bound uremic toxins p-cresylsulfate, p-cresylglucuronide and indoxylsulfate on the cross-talk between leukocytes and the vessel wall. In: 49th ERA-EDTA congress Paris—Abstract FO035

  80. De Smet R, Van Kaer J, Van Vlem B et al (2003) Toxicity of free p-cresol: a prospective and cross-sectional analysis. Clin Chem 49:470–478

    Article  PubMed  Google Scholar 

  81. Bammens B, Evenepoel P, Verbeke K, Vanrenterghem Y (2003) Removal of middle molecules and protein-bound solutes by peritoneal dialysis and relation with uremic symptoms. Kidney Int 64:2238–2243

    Article  PubMed  CAS  Google Scholar 

  82. Meijers BK, Bammens B, De MB, Verbeke K, Vanrenterghem Y, Evenepoel P (2008) Free p-cresol is associated with cardiovascular disease in hemodialysis patients. Kidney Int 73:1174–1180

    Article  PubMed  CAS  Google Scholar 

  83. Meijers BK, Claes K, Bammens B et al (2010) p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol 5:1182–1189

    Article  PubMed  CAS  Google Scholar 

  84. Bammens B, Evenepoel P, Keuleers H, Verbeke K, Vanrenterghem Y (2006) Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int 69:1081–1087

    Article  PubMed  CAS  Google Scholar 

  85. Wu IW, Hsu KH, Lee CC et al (2011) p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transpl 26:938–947

    Article  CAS  Google Scholar 

  86. Wang CP, Lu LF, Yu TH et al (2010) Serum levels of total p-cresylsulphate are associated with angiographic coronary atherosclerosis severity in stable angina patients with early stage of renal failure. Atherosclerosis 211:579–583

    Article  PubMed  CAS  Google Scholar 

  87. Chiu CA, Lu LF, Yu TH et al (2010) Increased levels of total P-Cresylsulphate and indoxyl sulphate are associated with coronary artery disease in patients with diabetic nephropathy. Rev Diabet Stud 7:275–284

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  89. Wu IW, Hsu KH, Hsu HJ et al (2012) 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

    Article  CAS  Google Scholar 

  90. Motojima M, Hosokawa A, Yamato H, Muraki T, Yoshioka T (2003) Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int 63:1671–1680

    Article  PubMed  CAS  Google Scholar 

  91. Nii-Kono T, Iwasaki Y, Uchida M et al (2007) Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells. Kidney Int 71:738–743

    Article  PubMed  CAS  Google Scholar 

  92. Faure V, Dou L, Sabatier F et al (2006) Elevation of circulating endothelial microparticles in patients with chronic renal failure. J Thromb Haemost 4:566–573

    Article  PubMed  CAS  Google Scholar 

  93. Peng YS, Lin YT, Chen Y, Hung KY, Wang SM (2012) Effects of indoxyl sulfate on adherens junctions of endothelial cells and the underlying signaling mechanism. J Cell Biochem 113:1034–1043

    Article  PubMed  CAS  Google Scholar 

  94. Yamamoto H, Tsuruoka S, Ioka T et al (2006) Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int 69:1780–1785

    Article  PubMed  CAS  Google Scholar 

  95. Lekawanvijit S, Adrahtas A, Kelly DJ, Kompa AR, Wang BH, Krum H (2010) Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J 31:1771–1779

    Article  PubMed  CAS  Google Scholar 

  96. Ito S, Osaka M, Higuchi Y, Nishijima F, Ishii H, Yoshida M (2010) Indoxyl sulfate induces leukocyte-endothelial interactions through up-regulation of E-selectin. J Biol Chem 285:38869–38875

    Article  PubMed  CAS  Google Scholar 

  97. Adijiang A, Goto S, Uramoto S, Nishijima F, Niwa T (2008) Indoxyl sulphate promotes aortic calcification with expression of osteoblast-specific proteins in hypertensive rats. Nephrol Dial Transpl 23:1892–1901

    Article  CAS  Google Scholar 

  98. Lee CT, Kuo CC, Chen YM et al (2010) Factors associated with blood concentrations of indoxyl sulfate and p-cresol in patients undergoing peritoneal dialysis. Perit Dial Int 30:456–463

    Article  PubMed  Google Scholar 

  99. Barreto FC, Barreto DV, Liabeuf S et al (2009) Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 4:1551–1558

    Article  PubMed  CAS  Google Scholar 

  100. Lesaffer G, De Smet R, Lameire N, Dhondt A, Duym P, Vanholder R (2000) Intradialytic removal of protein-bound uraemic toxins: role of solute characteristics and of dialyser membrane. Nephrol Dial Transpl 15:50–57

    Article  CAS  Google Scholar 

  101. Meijers BK, Weber V, Bammens B et al (2008) Removal of the uremic retention solute p-cresol using fractionated plasma separation and adsorption. Artif Organs 32:214–219

    Article  PubMed  CAS  Google Scholar 

  102. Meijers BK, Verhamme P, Nevens F et al (2007) Major coagulation disturbances during fractionated plasma separation and adsorption. Am J Transpl 7:2195–2199

    Article  CAS  Google Scholar 

  103. Evenepoel P, Bammens B, Verbeke K, Vanrenterghem Y (2006) Superior dialytic clearance of beta(2)-microglobulin and p-cresol by high-flux hemodialysis as compared to peritoneal dialysis. Kidney Int 70:794–799

    Article  PubMed  CAS  Google Scholar 

  104. Pham NM, Recht NS, Hostetter TH, Meyer TW (2008) Removal of the protein-bound solutes indican and p-cresol sulfate by peritoneal dialysis. Clin J Am Soc Nephrol 3:85–90

    Article  PubMed  CAS  Google Scholar 

  105. Lameire N, Vanholder R, De Smet R (2001) Uremic toxins and peritoneal dialysis. Kidney Int Suppl 78:S292–S297

    Article  PubMed  CAS  Google Scholar 

  106. Vanholder R, Meert N, Van Biesen W et al (2009) Why do patients on peritoneal dialysis have low blood levels of protein-bound solutes? Nat Clin Pract Nephrol 5:130–131

    Article  PubMed  Google Scholar 

  107. Schepers E, Glorieux G, Vanholder R (2010) The gut: the forgotten organ in uremia? Blood Purif 29:130–136

    Article  PubMed  Google Scholar 

  108. Bammens B, Verbeke K, Vanrenterghem Y, Evenepoel P (2003) Evidence for impaired assimilation of protein in chronic renal failure. Kidney Int 64:2196–2203

    Article  PubMed  CAS  Google Scholar 

  109. Aronov PA, Luo FJ, Plummer NS et al (2011) Colonic contribution to uremic solutes. J Am Soc Nephrol 22:1769–1776

    Article  PubMed  CAS  Google Scholar 

  110. Birkett A, Muir J, Phillips J, Jones G, O’Dea K (1996) Resistant starch lowers fecal concentrations of ammonia and phenols in humans. Am J Clin Nutr 63:766–772

    PubMed  CAS  Google Scholar 

  111. Meijers BK, De Preter V, Verbeke K, Vanrenterghem Y, Evenepoel P (2010) p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transpl 25:219–224

    Article  CAS  Google Scholar 

  112. Nakabayashi I, Nakamura M, Kawakami K et al (2011) Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study. Nephrol Dial Transpl 26:1094–1098

    Article  CAS  Google Scholar 

  113. Schulman G, Agarwal R, Acharya M, Berl T, Blumenthal S, Kopyt N (2006) A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD. Am J Kidney Dis 47:565–577

    Article  PubMed  CAS  Google Scholar 

  114. Niwa T, Ise M, Miyazaki T, Meada K (1993) Suppressive effect of an oral sorbent on the accumulation of p-cresol in the serum of experimental uremic rats. Nephron 65:82–87

    Article  PubMed  CAS  Google Scholar 

  115. Kikuchi K, Itoh Y, Tateoka R, Ezawa A, Murakami K, Niwa T (2010) Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry. J Chromatogr, B: Anal Technol Biomed Life Sci 878:2997–3002

    Article  CAS  Google Scholar 

  116. Deguchi T, Ohtsuki S, Otagiri M et al (2002) Major role of organic anion transporter 3 in the transport of indoxyl sulfate in the kidney. Kidney Int 61:1760–1768

    Article  PubMed  CAS  Google Scholar 

  117. Enomoto A, Takeda M, Tojo A et al (2002) Role of organic anion transporters in the tubular transport of indoxyl sulfate and the induction of its nephrotoxicity. J Am Soc Nephrol 13:1711–1720

    Article  PubMed  CAS  Google Scholar 

  118. Toyohara T, Suzuki T, Morimoto R et al (2009) SLCO4C1 transporter eliminates uremic toxins and attenuates hypertension and renal inflammation. J Am Soc Nephrol 20:2546–2555

    Article  PubMed  CAS  Google Scholar 

  119. Mutsaers HA, van den Heuvel LP, Ringens LH et al (2011) Uremic toxins inhibit transport by breast cancer resistance protein and multidrug resistance protein 4 at clinically relevant concentrations. PLoS One 6:e18438

    Article  PubMed  CAS  Google Scholar 

  120. Niwa T, Ise M (1994) Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med 124:96–104

    PubMed  CAS  Google Scholar 

  121. Niwa T, Ise M, Miyazaki T (1994) Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am J Nephrol 14:207–212

    Article  PubMed  CAS  Google Scholar 

  122. Niwa T, Tsukushi S, Ise M et al (1997) Indoxyl sulfate and progression of renal failure: effects of a low-protein diet and oral sorbent on indoxyl sulfate production in uremic rats and undialyzed uremic patients. Miner Electrolyte Metab 23:179–184

    PubMed  CAS  Google Scholar 

  123. Motojima M, Nishijima F, Ikoma M et al (1991) Role for “uremic toxin” in the progressive loss of intact nephrons in chronic renal failure. Kidney Int 40:461–469

    Article  PubMed  CAS  Google Scholar 

  124. Ueda H, Shibahara N, Takagi S, Inoue T, Katsuoka Y (2007) AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases. Ther Apher Dial 11:189–195

    Article  PubMed  CAS  Google Scholar 

  125. Akizawa T, Asano Y, Morita S et al (2009) Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial. Am J Kidney Dis 54:459–467

    Article  PubMed  CAS  Google Scholar 

  126. Shoji T, Wada A, Inoue K et al (2007) Prospective randomized study evaluating the efficacy of the spherical adsorptive carbon AST-120 in chronic kidney disease patients with moderate decrease in renal function. Nephron Clin Pract 105:c99–c107

    Article  PubMed  CAS  Google Scholar 

  127. Konishi K, Nakano S, Tsuda S, Nakagawa A, Kigoshi T, Koya D (2008) AST-120 (Kremezin) initiated in early stage chronic kidney disease stunts the progression of renal dysfunction in type 2 diabetic subjects. Diabetes Res Clin Pract 81:310–315

    Article  PubMed  CAS  Google Scholar 

  128. Ueda H, Shibahara N, Takagi S, Inoue T, Katsuoka Y (2008) AST-120 treatment in pre-dialysis period affects the prognosis in patients on hemodialysis. Ren Fail 30:856–860

    Article  PubMed  CAS  Google Scholar 

  129. Eloot S, Schepers E, Barreto DV et al (2011) Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol 6:1266–1273

    Article  PubMed  Google Scholar 

  130. Vanholder R, Eloot S, Schepers E, Neirynck N, Glorieux G, Massy Z (2012) An Obituary for GFR as the main marker for kidney function? Semin Dial 25:9–14

    Article  PubMed  Google Scholar 

  131. Neirynck N, Eloot S, Glorieux G et al (2012) Estimated glomerular filtration rate does not associate with the concentration of low molecular weight proteins in chronic kidney disease. In: 49th ERA-EDTA congress, Paris—Abstract SAP192

  132. Cooper BA, Branley P, Bulfone L et al (2010) A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 363:609–619

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Nephrology Section, 0K12, Department of Internal Medicine, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    N. Neirynck, R. Vanholder, E. Schepers, S. Eloot, A. Pletinck & G. Glorieux

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  1. N. Neirynck
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  2. R. Vanholder
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  3. E. Schepers
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  4. S. Eloot
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  5. A. Pletinck
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  6. G. Glorieux
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Correspondence to R. Vanholder.

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Neirynck, N., Vanholder, R., Schepers, E. et al. An update on uremic toxins. Int Urol Nephrol 45, 139–150 (2013). https://doi.org/10.1007/s11255-012-0258-1

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