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  • Review Article
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Cardiovascular disease in haemodialysis: role of the intravascular innate immune system

Nature Reviews Nephrology volume 13, pages 285–296 (2017)Cite this article

Subjects

Key Points

  • Haemodialysis is a life-saving renal replacement modality for end-stage renal disease, but this therapy is associated with an increased risk of cardiovascular disease

  • The biomaterial surfaces that come into contact with blood in the extracorporeal circuit during haemodialysis trigger activation of the intravascular cascade systems

  • Generation of activation products from the intravascular cascade systems causes systemic inflammation involving blood cells and the vascular tree

  • The anaphylatoxins C3a and C5a, bradykinin, thrombin and factor Xa can induce activation of endothelial cells and the vascular wall

  • The thrombotic and inflammatory properties of these activation products lead to atherogenesis, which can progress to arteriosclerosis and cardiovascular disease

Abstract

Haemodialysis is a life-saving renal replacement modality for end-stage renal disease, but this therapy also represents a major challenge to the intravascular innate immune system, which is comprised of the complement, contact and coagulation systems. Chronic inflammation is strongly associated with cardiovascular disease (CVD) in patients on haemodialysis. Biomaterial-induced contact activation of proteins within the plasma cascade systems occurs during haemodialysis and initially leads to local generation of inflammatory mediators on the biomaterial surface. The inflammation is spread by soluble activation products and mediators that are generated during haemodialysis and transported in the extracorporeal circuit back into the patient together with activated leukocytes and platelets. The combined effect is activation of the endothelium of the cardiovascular system, which loses its anti-thrombotic and anti-inflammatory properties, leading to atherogenesis and arteriosclerosis. This concept suggests that maximum suppression of the intravascular innate immune system is needed to minimize the risk of CVD in patients on haemodialysis. A potential approach to achieve this goal is to treat patients with broad-specificity systemic drugs that target more than one of the intravascular cascade systems. Alternatively, 'stealth' biomaterials that cause minimal cascade system activation could be used in haemodialysis circuits.

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Figure 1: Antithrombotic and anti-inflammatory properties of endothelial cells.
Figure 2: Overview of the complement system.
Figure 3: Activation of the contact system, kallikrein/kinin pathway and coagulation system.
Figure 4: Cascade system activation on a biomaterial surface.
Figure 5: Model of innate immunity activation as a cause of cardiovascular disease during dialysis.

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Acknowledgements

The authors thank Deborah McClellan for editing the manuscript before submission and Osama Hamad (Uppsala University, Sweden) for excellent help with drafting the figures. The authors' work was supported by grant 2013-65X-05647-34-4 from the Swedish Research Council (VR), the European Community's Seventh Framework Programme under the grant agreement n°602699 (DIREKT), and faculty grants from the Linnæus University, Sweden.

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, SE-751 85, Sweden

    Kristina N. Ekdahl & Bo Nilsson

  2. Linnæus Center of Biomaterials Chemistry, Linnæus University, Kalmar, SE-391 82, Sweden

    Kristina N. Ekdahl

  3. Department of Medical Sciences, Uppsala University, Uppsala, SE-75185, Sweden

    Inga Soveri & Bengt Fellström

  4. Department of Chemistry, Ångström Laboratory, Uppsala University, SE-751 21, Sweden

    Jöns Hilborn

Authors
  1. Kristina N. Ekdahl
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  2. Inga Soveri
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  3. Jöns Hilborn
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  4. Bengt Fellström
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  5. Bo Nilsson
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Contributions

All authors researched data for the article, discussed the content, wrote the text and reviewed or edited the manuscript before submission.

Corresponding author

Correspondence to Bo Nilsson.

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The authors declare no competing financial interests.

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Ekdahl, K., Soveri, I., Hilborn, J. et al. Cardiovascular disease in haemodialysis: role of the intravascular innate immune system. Nat Rev Nephrol 13, 285–296 (2017). https://doi.org/10.1038/nrneph.2017.17

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