Blood Purif 2010;29:114–120
(DOI:10.1159/000245636)

Immune Mechanisms Involved in Cardiovascular Complications of Chronic Kidney Disease

Stinghen A.E.M.a, b · Bucharles S.a · Riella M.C.a · Pecoits-Filho R.a
aCenter for Health and Biological Sciences, Pontifícia Universidade Católica do Paraná, and bBasic Pathology Department, Universidade Federal do Paraná, Curitiba, Brazil
email Corresponding Author


 goto top of outline Key Words

  • Chronic kidney disease, inflammation
  • Cardiovascular disease
  • Myocardiopathy
  • Atherosclerosis

 goto top of outline Abstract

A sustained status of chronic inflammation is closely linked to several complications of chronic kidney disease (CKD), such as vascular degeneration, myocardial fibrosis, loss of appetite, insulin resistance, increased muscle catabolism and anemia. These consequences of a chronically activated immune system impact on the acceleration of atherosclerosis, vascular calcification and development of heart dysfunction. Recent evidence suggests that these immune-mediated consequences of uremic toxicity are not only important to stratify the risk and understand the mechanisms of disease, but also represent an important area for intervention. Thus, the aim of this brief review is to discuss the immune mechanisms behind atherosclerosis and myocardiopathy in CKD. We also display the emerging evidence that strategies focusing on modulating the immune response or reducing the generation of triggers of inflammation may represent an important tool to reduce mortality in this group of patients. Ongoing studies may generate the evidence that will translate these strategies to definitive changes in clinical practice.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Hauser AB, Stinghen AE, Kato S, Bucharles S, Aita C, Yuzawa Y, et al: Characteristics and causes of immune dysfunction related to uremia and dialysis. Perit Dial Int 2008;28(suppl 3):S183–S187.
  2. Cohen G, Glorieux G, Thornalley P, Schepers E, Meert N, Jankowski J, et al: Review on uraemic toxins. III. Recommendations for handling uraemic retention solutes in vitro towards a standardized approach for research on uraemia. Nephrol Dial Transplant 2007;22:3381–3390.
  3. Kato S, Chmielewski M, Honda H, Pecoits-Filho R, Matsuo S, Yuzawa Y, et al: Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3:1526–1533.
  4. Li AC, Glass CK: The macrophage foam cell as a target for therapeutic intervention. Nat Med 2002;8:1235–1242.
  5. Libby P: Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844–2850.
  6. Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002;105:1135–1143.
  7. Bro S, Moeller F, Andersen CB, Olgaard K, Nielsen LB: Increased expression of adhesion molecules in uremic atherosclerosis in apolipoprotein-E-deficient mice. J Am Soc Nephrol 2004;15:1495–1503.
  8. Gonzalez MA, Selwyn AP: Endothelial function, inflammation, and prognosis in cardiovascular disease. Am J Med 2003;115(suppl 8A):99S–106S.
  9. Segal MS, Baylis C, Johnson RJ: Endothelial health and diversity in the kidney. J Am Soc Nephrol 2006;17:323–324.
  10. Diaz-Buxo JA, Woods HF: Protecting the endothelium: a new focus for management of chronic kidney disease. Hemodial Int 2006;10:42–48.
  11. Bhagat K, Vallance P: Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 1997;96:3042–3047.
  12. Zwaka PT, Hombach V, Torzewski J: C-reactive protein-mediated low density lipoprotein uptake by macrophages. Circulation 2001;103:1194–1202.
  13. Stinghen AE, Goncalves SM, Martines EG, Nakao LS, Riella MC, Aita CA, et al: Increased plasma and endothelial cell expression of chemokines and adhesion molecules in chronic kidney disease. Nephron Clin Pract 2009;111:c117–c126.
  14. Stenvinkel P, Carrero JJ, Axelsson J, Lindholm B, Heimburger O, Massy Z: Emerging biomarkers for evaluating cardiovascular risk in the chronic kidney disease patient: how do new pieces fit into the uremic puzzle? Clin J Am Soc Nephrol 2008;3:505–521.
  15. Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ, Allen J: Plasma concentrations of soluble intercellular adhesion molecule 1 and risk of future myocardial infarction in apparently healthy men. Lancet 1998;351:88–92.
  16. Stenvinkel P, Lindholm B, Heimburger M, Heimburger O: Elevated serum levels of soluble adhesion molecules predict death in pre-dialysis patients: association with malnutrition, inflammation, and cardiovascular disease. Nephrol Dial Transplant 2000;15:1624–1630.
  17. Silberberg JS, Barre PE, Prichard SS, Sniderman AD: Impact of left ventricular hypertrophy on survival in end-stage renal disease. Kidney Int 1989;36:286–290.
  18. London GM: Left ventricular alterations and end-stage renal disease. Nephrol Dial Transplant 2002;17(suppl 1):29–36.
  19. Ritz E: Left ventricular hypertrophy in renal disease: beyond preload and afterload. Kidney Int 2009;75:771–773.
  20. Gross ML, Ritz E: Hypertrophy and fibrosis in the cardiomyopathy of uremia – beyond coronary heart disease. Semin Dial 2008;21:308–318.
  21. Tyralla K, Amann K: Morphology of the heart and arteries in renal failure. Kidney Int Suppl 2003;84:S80–S83.
  22. Schunkert H, Hense HW: Molecular genetics of cardiovascular diseases (in German). Dtsch Med Wochenschr 1995;120:533–539.
  23. Zoccali C, Benedetto FA, Mallamaci F, Tripepi G, Giacone G, Stancanelli B, et al: Left ventricular mass monitoring in the follow-up of dialysis patients: prognostic value of left ventricular hypertrophy progression. Kidney Int 2004;65:1492–1498.
  24. Sharma S, Elliott PM, Whyte G, Mahon N, Virdee MS, Mist B, et al: Utility of metabolic exercise testing in distinguishing hypertrophic cardiomyopathy from physiologic left ventricular hypertrophy in athletes. J Am Coll Cardiol 2000;36:864–870.
  25. Santoro A, Mancini E, Basile C, Amoroso L, Di Giulio S, Usberti M, et al: Blood volume controlled hemodialysis in hypotension-prone patients: a randomized, multicenter controlled trial. Kidney Int 2002;62:1034–1045.
  26. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL: Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201–1206.
  27. Lopez D, Rodriguez-Sinovas A, Agullo L, Inserte J, Cabestrero A, Garcia-Dorado D: Acidic reoxygenation protects against endothelial dysfunction in rat aortic rings submitted to simulated ischemia. Am J Physiol Heart Circ Physiol 2008;295:H2409–H2416.
  28. Sato Y, Takatsu Y, Kataoka K, Yamada T, Taniguchi R, Sasayama S, et al: Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation. Clin Cardiol 1999;22:811–813.
  29. Niebauer J, Volk HD, Kemp M, Dominguez M, Schumann RR, Rauchhaus M, et al: Endotoxin and immune activation in chronic heart failure: a prospective cohort study. Lancet 1999;353:1838–1842.
  30. Goncalves S, Pecoits-Filho R, Perreto S, Barberato SH, Stinghen AE, Lima EG, et al: Associations between renal function, volume status and endotoxaemia in chronic kidney disease patients. Nephrol Dial Transplant 2006;21:2788–2794.
  31. Gonzalez EA, Sachdeva A, Oliver DA, Martin KJ: Vitamin D insufficiency and deficiency in chronic kidney disease: a single center observational study. Am J Nephrol 2004;24:503–510.
  32. Park MS, Lee HB: AGE accumulation in peritoneal membrane and cavity during peritoneal dialysis and its effect on peritoneal structure and function. Perit Dial Int 1999;19(suppl 2):S53–S57.

    External Resources

  33. Teng M, Wolf M, Ofsthun MN, Lazarus JM, Hernan MA, Camargo CA Jr, et al: Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005;16:1115–1125.
  34. Panichi V, Tetta C, Rindi P, Palla R, Lonnemann G: Plasma C-reactive protein is linked to backfiltration associated interleukin-6 production. Asaio J 1998;44:M415–M417.
  35. Valdivielso JM, Ayus JC: Role of vitamin D receptor activators on cardiovascular risk. Kidney Int Suppl 2008;111:S44–S49.
  36. Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353:238–248.
  37. Drueke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, et al: Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071–2084.
  38. Zannad F, Kessler M, Lehert P, Grunfeld JP, Thuilliez C, Leizorovicz A, et al: Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies. Kidney Int 2006;70:1318–1324.
  39. Takahashi A, Takase H, Toriyama T, Sugiura T, Kurita Y, Ueda R, et al: Candesartan, an angiotensin II type-1 receptor blocker, reduces cardiovascular events in patients on chronic haemodialysis – a randomized study. Nephrol Dial Transplant 2006;21:2507–2512.
  40. Suzuki H, Kanno Y, Sugahara S, Ikeda N, Shoda J, Takenaka T, et al: Effect of angiotensin receptor blockers on cardiovascular events in patients undergoing hemodialysis: an open-label randomized controlled trial. Am J Kidney Dis 2008;52:501–506.
  41. Seliger SL, Weiss NS, Gillen DL, Kestenbaum B, Ball A, Sherrard DJ, et al: HMG-CoA reductase inhibitors are associated with reduced mortality in ESRD patients. Kidney Int. 2002;61:297–304.
  42. Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al: Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395–1407.
  43. Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, et al: Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000;356:1213–1218.
  44. Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W: The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial. Circulation 2003;107:992–995.
  45. Andress DL: Vitamin D in chronic kidney disease: a systemic role for selective vitamin D receptor activation. Kidney Int 2006;69:33–43.
  46. Lee P, Peng H, Gelbart T, Wang L, Beutler E: Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 2005;102:1906–1910.
  47. Szeto CC, Kwan BC, Chow KM, Lai KB, Chung KY, Leung CB, et al: Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clin J Am Soc Nephrol 2008;3:431–436.
  48. Perianayagam MC, Jaber BL: Endotoxin-binding affinity of sevelamer hydrochloride. Am J Nephrol 2008;28:802–807.
  49. Ferramosca E, Burke S, Chasan-Taber S, Ratti C, Chertow GM, Raggi P: Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J 2005;149:820–825.
  50. Stinghen AEM, Goncalves SM, Bucharles S, Branco FS, Gruber B, Hauser A, Pecoits-Filho R: Sevelamer decreases systemic inflammation through its endotoxin binding effects. Blood Purif, submitted.

 goto top of outline Author Contacts

Roberto Pecoits-Filho, MD, PhD
Centro de Ciências Biológicas e da Saúde
Rua Imaculada Conceição 1155
Curitiba, PR 80215-901 (Brazil)
Tel./Fax +55 41 32 11657, E-Mail r.pecoits@pucpr.br


 goto top of outline Article Information

Published online: January 8, 2010
Number of Print Pages : 7
Number of Figures : 1, Number of Tables : 0, Number of References : 50


 goto top of outline Publication Details

Blood Purification

Vol. 29, No. 2, Year 2010 (Cover Date: January 2010)

Journal Editor: Ronco C. (Vicenza)
ISSN: 0253-5068 (Print), eISSN: 1421-9735 (Online)

For additional information: http://www.karger.com/BPU


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