Intradialytic Complement Activation Precedes the Development of Cardiovascular Events in Hemodialysis Patients

Felix Poppelaars*, Mariana Gaya da Costa, Bernardo Faria, Stefan P. Berger, Solmaz Assa, Mohamed R. Daha, Jose Osmar Medina Pestana, Willem J. van Son, Casper F. M. Franssen, Marc A. Seelen

*Corresponding author for this work

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Abstract

Background: Hemodialysis (HD) is a life-saving treatment for patients with end stage renal disease. However, HD patients have markedly increased rates of cardiovascular morbidity and mortality. Previously, a link between the complement system and cardiovascular events (CV-events) has been reported. In HD, systemic complement activation occurs due to blood-to-membrane interaction. We hypothesize that HD-induced complement activation together with inflammation and thrombosis are involved in the development of CV-events in these patients.

Methods: HD patients were followed for the occurrence of CV-events during a maximum follow-up of 45 months. Plasma samples were collected from 55 patients at different time points during one HD session prior to follow-up. Plasma levels of mannose-binding lectin, properdin and C3d/C3 ratios were assessed by ELISA. In addition, levels of von Willebrand factor, TNF-alpha and IL-6/IL-10 ratios were determined. An ex-vivo model of HD was used to assess the effect of complement inhibition.

Results: During median follow-up of 32 months, 17 participants developed CV-events. In the CV-event group, the C3d/C3-ratio sharply increased 30 min after the start of the HD session, while in the event-free group the ratio did not increase. In accordance, HD patients that developed a CV-event also had a sustained higher IL-6/IL-10-ratio during the first 60 min of the HD session, followed by a greater rise in TNF-alpha levels and von Willebrand factor at the end of the session. In the ex-vivo HD model, we found that complement activation contributed to the induction of TNF-alpha levels, IL-6/IL-10-ratio and levels of von Willebrand factor.

Conclusions: In conclusion, these findings suggest that early intradialytic complement activation predominantly occurred in HD patients who develop a CV-event during follow-up. In addition, in these patients complement activation was accompanied by a pro-inflammatory and pro-thrombotic response. Experimental complement inhibition revealed that this reaction is secondary to complement activation. Therefore, our data suggests that HD-induced complement, inflammation and coagulation are involved in the increased CV risk of HD patients.

Original languageEnglish
Article number2070
Number of pages11
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - 13-Sep-2018

Keywords

  • complement
  • kidney
  • cardiovascular risk
  • hemodialysis
  • biocompatibility
  • innate immunity
  • C1-inhibitor
  • VENTRICULAR SYSTOLIC DYSFUNCTION
  • RENAL REPLACEMENT THERAPY
  • CHRONIC KIDNEY-DISEASE
  • ALL-CAUSE MORTALITY
  • PROGNOSTIC-SIGNIFICANCE
  • INDUCED INFLAMMATION
  • DIALYSIS MEMBRANES
  • IMMUNE-SYSTEM
  • RISK-FACTOR
  • CYTOKINE

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