Skip to main content
SpringerLink
Log in

Novel Combination Therapy to Target Heart and Kidney

  • Chapter
  • First Online:
Cardio-Renal Clinical Challenges

Abstract

Due to a significant burden of the common coexistence of chronic kidney disease (CKD) and cardiovascular disease (CVD) as well as their complex pathophysiological interplay, the concept of integrated cardiorenal pathology has been increasingly recognized. A continuing increase in prevalence of CKD has become a global health concern. One of the major consequences of the growing CKD population is a further deterioration of the CVD epidemic. CKD patients are at extraordinarily high risk for CVD; and CVD in turn is the single most common cause of death in the CKD population, especially in the dialysis-dependent subgroup. Interestingly, traditional cardiovascular risk factors are not sufficient to explain the high prevalence of CVD in this population. There have thus been major efforts in search of novel risk factors specific or closely-related to the CKD milieu. Evidence of non-dialyzable protein-bound uremic toxins as potential risk factors for CKD-associated cardiovascular pathology and mortality as well as potential strategies targeting these toxins has emerged in recent years. At present, indoxyl sulfate and p-cresyl sulfate are the two most problematic toxins with regard to their negative cardiorenal impact. Along with ongoing development in dialysis technique to improve removal of these toxins, novel therapies that reduce the production of such toxins offer a potential approach to alleviating, or even preventing, their toxic effects on heart and kidney.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CKD:

Chronic kidney disease

CV:

Cardiovascular

CVD:

Cardiovascular disease

ESRD:

End-stage renal disease

HD:

Hemodialysis

IL:

Interleukin

IS:

Indoxyl sulfate

LVH:

Left ventricular hypertrophy

MAPK:

Mitogen-activated protein kinase

MW:

Molecular weight

OAT:

Organic anion transporter

PBUT:

Protein-bound uremic toxin

pCS:

p-cresyl sulfate

ROS:

Reactive oxygen species

TGF-β1:

Transforming growth factor-β1

TNF:

Tumor necrosis factor

References

  1. U.S. Renal Data System, USRDS. Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007.

    Google Scholar 

  2. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2005;67:2089–100.

    PubMed  Google Scholar 

  3. Keith DS, Nichols GA, Gullion CM, et al. Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med. 2004;164:659–63.

    PubMed  Google Scholar 

  4. Sarnak MJ, Levey AS, Schoolwerth AC, et al. 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. Circulation. 2003;108:2154–69.

    PubMed  Google Scholar 

  5. Schrier RW. Cardiorenal versus renocardiac syndrome: is there a difference? Nat Clin Pract Nephrol. 2007;3:637.

    PubMed  Google Scholar 

  6. Lindner A, Charra B, Sherrard DJ, et al. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med. 1974;290:697–701.

    CAS  PubMed  Google Scholar 

  7. Rostand SG, Kirk KA, Rutsky EA. Dialysis-associated ischemic heart disease: insights from coronary angiography. Kidney Int. 1984;25:653–9.

    CAS  PubMed  Google Scholar 

  8. U.S. Renal Data System, USRDS. Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2012.

    Google Scholar 

  9. Glassock RJ, Pecoits-Filho R, Barberato SH. Left ventricular mass in chronic kidney disease and ESRD. Clin J Am Soc Nephrol. 2009;4 Suppl 1:S79–91.

    PubMed  Google Scholar 

  10. Amann K, Neususs R, Ritz E, et al. Changes of vascular architecture independent of blood pressure in experimental uremia. Am J Hypertens. 1995;8:409–17.

    CAS  PubMed  Google Scholar 

  11. Aoki J, Ikari Y, Nakajima H, et al. Clinical and pathologic characteristics of dilated cardiomyopathy in hemodialysis patients. Kidney Int. 2005;67:333–40.

    PubMed  Google Scholar 

  12. Guerin AP, Pannier B, Marchais SJ, et al. Cardiovascular disease in the dialysis population: prognostic significance of arterial disorders. Curr Opin Nephrol Hypertens. 2006;15:105–10.

    PubMed  Google Scholar 

  13. U.S. Renal Data System, USRDS. Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2010.

    Google Scholar 

  14. Parfrey PS, Harnett JD, Foley RN, et al. Impact of renal transplantation on uremic cardiomyopathy. Transplantation. 1995;60:908–14.

    CAS  PubMed  Google Scholar 

  15. Okouchi Y, Arisaka H, Shimada A, et al. Improvement of left ventricular function after renal transplantation in a patient with uremic cardiomyopathy: report of a case. Surg Today. 1993;23:998–1002.

    CAS  PubMed  Google Scholar 

  16. Deng Y, Pandit A, Heilman RL, et al. Left ventricular torsion changes post kidney transplantation. J Cardiovasc Ultrasound. 2013;21:171–6.

    PubMed Central  PubMed  Google Scholar 

  17. Zoccali C, Benedetto FA, Mallamaci F, et al. Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression. Kidney Int. 2004;65:1492–8.

    PubMed  Google Scholar 

  18. London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and survival of patients receiving hemodialysis: follow-up of an interventional study. J Am Soc Nephrol. 2001;12:2759–67.

    CAS  PubMed  Google Scholar 

  19. Covic A, Goldsmith DJ, Georgescu G, et al. Echocardiographic findings in long-term, long-hour hemodialysis patients. Clin Nephrol. 1996;45:104–10.

    CAS  PubMed  Google Scholar 

  20. Gross ML, Ritz E. Hypertrophy and fibrosis in the cardiomyopathy of uremia–beyond coronary heart disease. Semin Dial. 2008;21:308–18.

    PubMed  Google Scholar 

  21. Wali RK, Wang GS, Gottlieb SS, et al. Effect of kidney transplantation on left ventricular systolic dysfunction and congestive heart failure in patients with end-stage renal disease. J Am Coll Cardiol. 2005;45:1051–60.

    PubMed  Google Scholar 

  22. Dhondt A, Vanholder R, Van Biesen W, et al. The removal of uremic toxins. Kidney Int Suppl. 2000;76:S47–59.

    CAS  PubMed  Google Scholar 

  23. Vanholder R, De Smet R, Glorieux G, et al. Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int. 2003;63:1934–43.

    CAS  PubMed  Google Scholar 

  24. Ikegaya K, Nokihara K, Yasuhara T. Characterization of sulfhydryl heterogeneity in human serum albumin and recombinant human serum albumin for clinical use. Biosci Biotechnol Biochem. 2010;74:2232–6.

    CAS  PubMed  Google Scholar 

  25. Moradi H, Sica DA, Kalantar-Zadeh K. Cardiovascular burden associated with uremic toxins in patients with chronic kidney disease. Am J Nephrol. 2013;38:136–48.

    CAS  PubMed  Google Scholar 

  26. Wu IW, Hsu KH, Lee CC, et al. p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease. Nephrol Dial Transplant. 2011;26:938–47.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Barreto FC, Barreto DV, Liabeuf S, et al. Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol. 2009;4:1551–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Wu IW, Hsu KH, Hsu HJ, et al. Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients–a prospective cohort study. Nephrol Dial Transplant. 2012;27:1169–75.

    CAS  PubMed  Google Scholar 

  29. Liabeuf S, Barreto DV, Barreto FC, et al. Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant. 2010;25:1183–91.

    CAS  PubMed  Google Scholar 

  30. Bammens B, Evenepoel P, Keuleers H, et al. Free serum concentrations of the protein-bound retention solute p-cresol predict mortality in hemodialysis patients. Kidney Int. 2006;69:1081–7.

    CAS  PubMed  Google Scholar 

  31. Meijers BK, Claes K, Bammens B, et al. p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol. 2010;5:1182–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Moustapha A, Naso A, Nahlawi M, et al. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation. 1998;97:138–41.

    CAS  PubMed  Google Scholar 

  33. de Loor H, Bammens B, Evenepoel P, et al. Gas chromatographic-mass spectrometric analysis for measurement of p-cresol and its conjugated metabolites in uremic and normal serum. Clin Chem. 2005;51:1535–8.

    PubMed  Google Scholar 

  34. Lekawanvijit S, Adrahtas A, Kelly DJ, et al. Does indoxyl sulfate, a uraemic toxin, have direct effects on cardiac fibroblasts and myocytes? Eur Heart J. 2010;31:1771–9.

    CAS  PubMed  Google Scholar 

  35. Dou L, Bertrand E, Cerini C, et al. The uremic solutes p-cresol and indoxyl sulfate inhibit endothelial proliferation and wound repair. Kidney Int. 2004;65:442–51.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Miyazaki T, Ise M, Seo H, et al. Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys. Kidney Int Suppl. 1997;62:S15–22.

    CAS  PubMed  Google Scholar 

  38. Miyazaki T, Aoyama I, Ise M, et al. An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys. Nephrol Dial Transplant. 2000;15:1773–81.

    CAS  PubMed  Google Scholar 

  39. Dou L, Jourde-Chiche N, Faure V, et al. The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells. J Thromb Haemost. 2007;5:1302–8.

    CAS  PubMed  Google Scholar 

  40. Sun CY, Hsu HH, Wu MS. p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol Dial Transplant. 2013;28(1):70–8.

    CAS  PubMed  Google Scholar 

  41. Niwa T, Ise M, Miyazaki T. Progression of glomerular sclerosis in experimental uremic rats by administration of indole, a precursor of indoxyl sulfate. Am J Nephrol. 1994;14:207–12.

    CAS  PubMed  Google Scholar 

  42. Lekawanvijit S, Kompa AR, Manabe M, et al. Chronic kidney disease-induced cardiac fibrosis is ameliorated by reducing circulating levels of a non-dialysable uremic toxin, indoxyl sulfate. PLoS One. 2012;7:e41281.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Yu M, Kim YJ, Kang DH. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clin J Am Soc Nephrol. 2011;6:30–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Tamada S, Asai T, Kuwabara N, et al. Molecular mechanisms and therapeutic strategies of chronic renal injury: the role of nuclear factor kappaB activation in the development of renal fibrosis. J Pharmacol Sci. 2006;100:17–21.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Sun CY, Chang SC, Wu MS. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int. 2012;81:640–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Yamamoto H, Tsuruoka S, Ioka T, et al. Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells. Kidney Int. 2006;69:1780–5.

    CAS  PubMed  Google Scholar 

  48. Motojima M, Hosokawa A, Yamato H, et al. Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-kappaB and free radical in proximal tubular cells. Kidney Int. 2003;63:1671–80.

    CAS  PubMed  Google Scholar 

  49. Gelasco AK, Raymond JR. Indoxyl sulfate induces complex redox alterations in mesangial cells. Am J Physiol Renal Physiol. 2006;290:F1551–8.

    CAS  PubMed  Google Scholar 

  50. Tumur Z, Niwa T. Oral sorbent AST-120 increases renal NO synthesis in uremic rats. J Ren Nutr. 2008;18:60–4.

    PubMed  Google Scholar 

  51. Owada S, Goto S, Bannai K, et al. Indoxyl sulfate reduces superoxide scavenging activity in the kidneys of normal and uremic rats. Am J Nephrol. 2008;28:446–54.

    CAS  PubMed  Google Scholar 

  52. Fujii H, Nishijima F, Goto S, et al. Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress. Nephrol Dial Transplant. 2009;24:2089–95.

    CAS  PubMed  Google Scholar 

  53. Adijiang A, Higuchi Y, Nishijima F, et al. Indoxyl sulfate, a uremic toxin, promotes cell senescence in aorta of hypertensive rats. Biochem Biophys Res Commun. 2010;399:637–41.

    CAS  PubMed  Google Scholar 

  54. Muteliefu G, Enomoto A, Jiang P, et al. Indoxyl sulphate induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. Nephrol Dial Transplant. 2009;24:2051–8.

    CAS  PubMed  Google Scholar 

  55. Shimizu H, Bolati D, Adijiang A, et al. Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor-kB. Am J Nephrol. 2011;33:319–24.

    CAS  PubMed  Google Scholar 

  56. Pletinck A, Glorieux G, Schepers E, et al. Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall. J Am Soc Nephrol. 2013;24:1981–94.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  58. Neirynck N, Vanholder R, Schepers E, et al. An update on uremic toxins. Int Urol Nephrol. 2013;45(1):139–50.

    CAS  PubMed  Google Scholar 

  59. Sanders JM, Bucher JR, Peckham JC, et al. Carcinogenesis studies of cresols in rats and mice. Toxicology. 2009;257:33–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Peng YS, Ding HC, Lin YT, et al. Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. Toxicology. 2012;302(1):11–7.

    CAS  PubMed  Google Scholar 

  61. Dou L, Cerini C, Brunet P, et al. P-cresol, a uremic toxin, decreases endothelial cell response to inflammatory cytokines. Kidney Int. 2002;62:1999–2009.

    CAS  PubMed  Google Scholar 

  62. Wu ZF, Liu GL, Zhou Z, et al. Induction of immune-related gene expression in Ctenopharyngodon idella kidney cells by secondary metabolites from immunostimulatory Alcaligenes faecalis FY-3. Scand J Immunol. 2012;76:131–40.

    CAS  PubMed  Google Scholar 

  63. Jourde-Chiche N, Dou L, Sabatier F, et al. Levels of circulating endothelial progenitor cells are related to uremic toxins and vascular injury in hemodialysis patients. J Thromb Haemost. 2009;7:1576–84.

    CAS  PubMed  Google Scholar 

  64. Satoh M, Hayashi H, Watanabe M, et al. Uremic toxins overload accelerates renal damage in a rat model of chronic renal failure. Nephron Exp Nephrol. 2003;95:e111–8.

    CAS  PubMed  Google Scholar 

  65. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.

    PubMed Central  PubMed  Google Scholar 

  66. Heinz J, Kropf S, Luley C, et al. Homocysteine as a risk factor for cardiovascular disease in patients treated by dialysis: a meta-analysis. Am J Kidney Dis. 2009;54:478–89.

    CAS  PubMed  Google Scholar 

  67. Thambyrajah J, Townend JN. Homocysteine and atherothrombosis–mechanisms for injury. Eur Heart J. 2000;21:967–74.

    CAS  PubMed  Google Scholar 

  68. Hofmann MA, Lalla E, Lu Y, et al. Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest. 2001;107:675–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Brown JC, Rosenquist TH, Monaghan DT. ERK2 activation by homocysteine in vascular smooth muscle cells. Biochem Biophys Res Commun. 1998;251:669–76.

    CAS  PubMed  Google Scholar 

  70. Van Campenhout A, Moran CS, Parr A, et al. Role of homocysteine in aortic calcification and osteogenic cell differentiation. Atherosclerosis. 2009;202:557–66.

    PubMed Central  PubMed  Google Scholar 

  71. Lee JC, Downing SE. Negative inotropic effects of phenol on isolated cardiac muscle. Am J Pathol. 1981;102:367–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. McGregor D. Hydroquinone: an evaluation of the human risks from its carcinogenic and mutagenic properties. Crit Rev Toxicol. 2007;37:887–914.

    CAS  PubMed  Google Scholar 

  73. Lekawanvijit S, Kompa AR, Wang BH, et al. Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res. 2012;111:1470–83.

    CAS  PubMed  Google Scholar 

  74. Taki K, Tsuruta Y, Niwa T. Indoxyl sulfate and atherosclerotic risk factors in hemodialysis patients. Am J Nephrol. 2007;27:30–5.

    CAS  PubMed  Google Scholar 

  75. Qin X, Huo Y, Langman CB, et al. Folic acid therapy and cardiovascular disease in ESRD or advanced chronic kidney disease: a meta-analysis. Clin J Am Soc Nephrol. 2011;6:482–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Mann JF, Sheridan P, McQueen MJ, et al. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease–results of the renal Hope-2 study. Nephrol Dial Transplant. 2008;23:645–53.

    CAS  PubMed  Google Scholar 

  77. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA. 2007;298:1163–70.

    CAS  PubMed  Google Scholar 

  78. House AA, Eliasziw M, Cattran DC, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA. 2010;303:1603–9.

    CAS  PubMed  Google Scholar 

  79. Liu S, Wang BH, Kompa AR, et al. Antagonists of organic anion transporters 1 and 3 ameliorate adverse cardiac remodelling induced by uremic toxin indoxyl sulfate. Int J Cardiol. 2012;158:457–8.

    PubMed  Google Scholar 

  80. Shimizu H, Bolati D, Higashiyama Y, et al. Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-kappaB, p53, ERK, and JNK in proximal tubular cells. Life Sci. 2012;90:525–30.

    CAS  PubMed  Google Scholar 

  81. Shimizu H, Bolati D, Adijiang A, et al. NF-kappaB plays an important role in indoxyl sulfate-induced cellular senescence, fibrotic gene expression, and inhibition of proliferation in proximal tubular cells. Am J Physiol Cell Physiol. 2011;301:C1201–12.

    CAS  PubMed  Google Scholar 

  82. Shimizu H, Bolati D, Adijiang A, et al. Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. Am J Physiol Cell Physiol. 2010;299:C1110–7.

    CAS  PubMed  Google Scholar 

  83. Babb AL, Farrell PC, Uvelli DA, et al. Hemodialyzer evaluation by examination of solute molecular spectra. Trans Am Soc Artif Intern Organs. 1972;18(98–105):122.

    Google Scholar 

  84. Babb AL, Popovich RP, Christopher TG, et al. The genesis of the square meter-hour hypothesis. Trans Am Soc Artif Intern Organs. 1971;17:81–91.

    CAS  PubMed  Google Scholar 

  85. Meert N, Eloot S, Waterloos MA, et al. Effective removal of protein-bound uraemic solutes by different convective strategies: a prospective trial. Nephrol Dial Transplant. 2009;24:562–70.

    CAS  PubMed  Google Scholar 

  86. Culleton BF, Walsh M, Klarenbach SW, et al. Effect of frequent nocturnal hemodialysis vs conventional hemodialysis on left ventricular mass and quality of life: a randomized controlled trial. JAMA. 2007;298:1291–9.

    CAS  PubMed  Google Scholar 

  87. Lesaffer G, De Smet R, Lameire N, et al. Intradialytic removal of protein-bound uraemic toxins: role of solute characteristics and of dialyser membrane. Nephrol Dial Transplant. 2000;15:50–7.

    CAS  PubMed  Google Scholar 

  88. Testa A, Gentilhomme H, Le Carrer D, et al. In vivo removal of high- and low-molecular-weight compounds in hemodiafiltration with on-line regeneration of ultrafiltrate. Nephron Clin Pract. 2006;104:c55–60.

    CAS  PubMed  Google Scholar 

  89. Friedman AN, Bostom AG, Levey AS, et al. Plasma total homocysteine levels among patients undergoing nocturnal versus standard hemodialysis. J Am Soc Nephrol. 2002;13:265–8.

    CAS  PubMed  Google Scholar 

  90. Heinz J, Domrose U, Westphal S, et al. Washout of water-soluble vitamins and of homocysteine during haemodialysis: effect of high-flux and low-flux dialyser membranes. Nephrology (Carlton). 2008;13:384–9.

    Google Scholar 

  91. Righetti M, Ferrario GM, Serbelloni P, et al. Homocysteine reduction rate in internal haemodiafiltration-a comparison with other mixed dialysis therapies. Nephrol Dial Transplant. 2006;21:2034–5.

    CAS  PubMed  Google Scholar 

  92. Ward RA. Protein-leaking membranes for hemodialysis: a new class of membranes in search of an application? J Am Soc Nephrol. 2005;16:2421–30.

    CAS  PubMed  Google Scholar 

  93. Winchester JF, Silberzweig J, Ronco C, et al. Sorbents in acute renal failure and end-stage renal disease: middle molecule and cytokine removal. Blood Purif. 2004;22:73–7.

    CAS  PubMed  Google Scholar 

  94. Dinh DC, Recht NS, Hostetter TH, et al. Coated carbon hemoperfusion provides limited clearance of protein-bound solutes. Artif Organs. 2008;32:717–24.

    CAS  PubMed  Google Scholar 

  95. Tijink MS, Wester M, Glorieux G, et al. Mixed matrix hollow fiber membranes for removal of protein-bound toxins from human plasma. Biomaterials. 2013;34:7819–28.

    CAS  PubMed  Google Scholar 

  96. Vaziri ND, Wong J, Pahl M, et al. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2012;83:308–15.

    PubMed  Google Scholar 

  97. Bammens B, Verbeke K, Vanrenterghem Y, et al. Evidence for impaired assimilation of protein in chronic renal failure. Kidney Int. 2003;64:2196–203.

    CAS  PubMed  Google Scholar 

  98. Wu MJ, Chang CS, Cheng CH, et al. Colonic transit time in long-term dialysis patients. Am J Kidney Dis. 2004;44:322–7.

    PubMed  Google Scholar 

  99. Hida M, Aiba Y, Sawamura S, et al. Inhibition of the accumulation of uremic toxins in the blood and their precursors in the feces after oral administration of Lebenin, a lactic acid bacteria preparation, to uremic patients undergoing hemodialysis. Nephron. 1996;74:349–55.

    CAS  PubMed  Google Scholar 

  100. Takayama F, Taki K, Niwa T. Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis. Am J Kidney Dis. 2003;41:S142–5.

    PubMed  Google Scholar 

  101. Taki K, Takayama F, Niwa T. Beneficial effects of Bifidobacteria in a gastroresistant seamless capsule on hyperhomocysteinemia in hemodialysis patients. J Ren Nutr. 2005;15:77–80.

    PubMed  Google Scholar 

  102. Ranganathan N, Ranganathan P, Friedman EA, et al. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Adv Ther. 2010;27:634–47.

    PubMed  Google Scholar 

  103. Meijers BK, De Preter V, Verbeke K, et al. p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrol Dial Transplant. 2010;25:219–24.

    CAS  PubMed  Google Scholar 

  104. Nakabayashi I, Nakamura M, Kawakami K, et al. Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients: a preliminary study. Nephrol Dial Transplant. 2011;26:1094–8.

    CAS  PubMed  Google Scholar 

  105. Marzocco S, Dal Piaz F, Di Micco L, et al. Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease. Blood Purif. 2013;35:196–201.

    CAS  PubMed  Google Scholar 

  106. Shen B, Pardi DS, Bennett AE, et al. The efficacy and tolerability of AST-120 (spherical carbon adsorbent) in active pouchitis. Am J Gastroenterol. 2009;104:1468–74.

    CAS  PubMed  Google Scholar 

  107. Aoyama I, Shimokata K, Niwa T. An oral adsorbent downregulates renal expression of genes that promote interstitial inflammation and fibrosis in diabetic rats. Nephron. 2002;92:635–51.

    CAS  PubMed  Google Scholar 

  108. Kikuchi K, Itoh Y, Tateoka R, et al. 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 Analyt Technol Biomed Life Sci. 2010;878:2997–3002.

    CAS  PubMed  Google Scholar 

  109. Yamagishi S, Nakamura K, Matsui T, et al. Oral administration of AST-120 (Kremezin) is a promising therapeutic strategy for advanced glycation end product (AGE)-related disorders. Med Hypotheses. 2007;69:666–8.

    CAS  PubMed  Google Scholar 

  110. Marier JF, Lee J, Kambhampati SR, et al. Effect of repeated oral administrations of the oral adsorbent AST-120 on serum creatinine and other markers of renal function. A randomized controlled study in patients with chronic kidney disease. Am J Nephrol. 2006;26:136–41.

    CAS  PubMed  Google Scholar 

  111. Aoyama I, Niwa T. An oral adsorbent ameliorates renal overload of indoxyl sulfate and progression of renal failure in diabetic rats. Am J Kidney Dis. 2001;37:S7–12.

    CAS  PubMed  Google Scholar 

  112. Nakagawa N, Hasebe N, Sumitomo K, et al. An oral adsorbent, AST-120, suppresses oxidative stress in uremic rats. Am J Nephrol. 2006;26:455–61.

    CAS  PubMed  Google Scholar 

  113. Sato T, Liang K, Vaziri ND. Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis. Kidney Int. 2003;64:1780–6.

    CAS  PubMed  Google Scholar 

  114. Kobayashi N, Maeda A, Horikoshi S, et al. Effects of oral adsorbent AST-120 (Kremezin) on renal function and glomerular injury in early-stage renal failure of subtotal nephrectomized rats. Nephron. 2002;91:480–5.

    CAS  PubMed  Google Scholar 

  115. Yamamoto S, Zuo Y, Ma J, et al. Oral activated charcoal adsorbent (AST-120) ameliorates extent and instability of atherosclerosis accelerated by kidney disease in apolipoprotein E-deficient mice. Nephrol Dial Transplant. 201;26(8):2491–7.

    Google Scholar 

  116. Ueda H, Shibahara N, Takagi S, et al. AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases. Ther Apher Dial. 2007;11:189–95.

    CAS  PubMed  Google Scholar 

  117. Ueda H, Shibahara N, Takagi S, et al. AST-120 treatment in pre-dialysis period affects the prognosis in patients on hemodialysis. Ren Fail. 2008;30:856–60.

    CAS  PubMed  Google Scholar 

  118. Konishi K, Nakano S, Tsuda S, et al. 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. 2008;81:310–5.

    CAS  PubMed  Google Scholar 

  119. Sanaka T, Akizawa T, Koide K, et al. Protective effect of an oral adsorbent on renal function in chronic renal failure: determinants of its efficacy in diabetic nephropathy. Ther Apher Dial. 2004;8:232–40.

    CAS  PubMed  Google Scholar 

  120. Hayashino Y, Fukuhara S, Akizawa T, et al. Cost-effectiveness of administering oral adsorbent AST-120 to patients with diabetes and advance-stage chronic kidney disease. Diabetes Res Clin Pract. 2010;90:154–9.

    PubMed  Google Scholar 

  121. Niwa T, Nomura T, Sugiyama S, et al. The protein metabolite hypothesis, a model for the progression of renal failure: an oral adsorbent lowers indoxyl sulfate levels in undialyzed uremic patients. Kidney Int Suppl. 1997;62:S23–8.

    CAS  PubMed  Google Scholar 

  122. Iida S, Kohno K, Yoshimura J, et al. Carbonic-adsorbent AST-120 reduces overload of indoxyl sulfate and the plasma level of TGF-beta1 in patients with chronic renal failure. Clin Exp Nephrol. 2006;10:262–7.

    CAS  PubMed  Google Scholar 

  123. Maeda K, Hamada C, Hayashi T, et al. Long-term effects of the oral adsorbent, AST-120, in patients with chronic renal failure. J Int Med Res. 2009;37:205–13.

    CAS  PubMed  Google Scholar 

  124. Nakamura T, Kawagoe Y, Matsuda T, et al. Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure. Kidney Blood Press Res. 2004;27:121–6.

    CAS  PubMed  Google Scholar 

  125. Goto S, Kitamura K, Kono K, et al. Association between AST-120 and abdominal aortic calcification in predialysis patients with chronic kidney disease. Clin Exp Nephrol. 2013;17:365–71.

    CAS  PubMed  Google Scholar 

  126. Nakai K, Fujii H, Kono K, et al. Effects of AST-120 on left ventricular mass in predialysis patients. Am J Nephrol. 2011;33:218–23.

    PubMed  Google Scholar 

  127. Tsubakihara Y, Takabatake Y, Oka K, et al. Effects of the oral adsorbent AST-120 on tryptophan metabolism in uremic patients. Am J Kidney Dis. 2003;41:S38–41.

    CAS  PubMed  Google Scholar 

  128. Sanaka T, Fujimoto K, Niwayama J, et al. Effect of combined treatment of oral sorbent with protein-restricted diet on change of reciprocal creatinine slope in patients with CRF. Am J Kidney Dis. 2003;41:S35–7.

    CAS  PubMed  Google Scholar 

  129. Owada A, Nakao M, Koike J, et al. Effects of oral adsorbent AST-120 on the progression of chronic renal failure: a randomized controlled study. Kidney Int Suppl. 1997;63:S188–90.

    CAS  PubMed  Google Scholar 

  130. Schulman G. A nexus of progression of chronic kidney disease: charcoal, tryptophan and profibrotic cytokines. Blood Purif. 2006;24:143–8.

    PubMed  Google Scholar 

  131. Niwa T, Tsukushi S, Ise M, et al. 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. 1997;23:179–84.

    CAS  PubMed  Google Scholar 

  132. Akizawa T, Asano Y, Morita S, et al. Effect of a carbonaceous oral adsorbent on the progression of CKD: a multicenter, randomized, controlled trial. Am J Kidney Dis. 2009;54:459–67.

    CAS  PubMed  Google Scholar 

  133. Schulman G, Berl T, Beck GJ, et al. EPPIC (Evaluating Prevention of Progression In Chronic Kidney Disease): results from 2 phase III, randomized, placebo-controlled, double-blind trials of AST-120 in adults with CKD [abstract]. J Am Soc Nephrol. 2012;23:7B.

    Google Scholar 

  134. Shibahara H, Shibahara N. Cardiorenal protective effect of the oral uremic toxin absorbent AST-120 in chronic heart disease patients with moderate CKD. J Nephrol. 2010;23:535–40.

    PubMed  Google Scholar 

  135. Lekawanvijit S, Kumfu S, Wang BH, et al. The uremic toxin adsorbent AST-120 abrogates cardiorenal injury following myocardial infarction. PLoS One. 2013;8:e83687.

    PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Chiang Mai University Hospital, 110 Intawaroros, Sribhoom, Chiang Mai, 50200, Thailand

    Suree Lekawanvijit MD, FRCPath, PhD

  2. Epidemiology and Preventive Medicine, Alfred Hospital, 99 Commercial Road, Melbourne, VIC, 3004, Australia

    Henry Krum MBBS, PhD, FRACP, FCSANZ, FESC

Authors
  1. Suree Lekawanvijit MD, FRCPath, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henry Krum MBBS, PhD, FRACP, FCSANZ, FESC
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suree Lekawanvijit MD, FRCPath, PhD .

Editor information

Editors and Affiliations

  1. Renal and Transplantation Department, Guy's Hospital, London, United Kingdom

    David Goldsmith

  2. Gr. T. Popa University of Medicine and Pharmacy, Iasi, Romania

    Adrian Covic

  3. Karolinska Institutet Danderyd University Hospital, Stockholm, Sweden

    Jonas Spaak

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Lekawanvijit, S., Krum, H. (2015). Novel Combination Therapy to Target Heart and Kidney. In: Goldsmith, D., Covic, A., Spaak, J. (eds) Cardio-Renal Clinical Challenges. Springer, Cham. https://doi.org/10.1007/978-3-319-09162-4_19

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-09162-4_19

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-09161-7

  • Online ISBN: 978-3-319-09162-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation