Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis

DeAngelis, Robert A.; Reis, Edimara S.; Ricklin, Daniel; Lambris, John D.

doi:10.1016/j.imbio.2012.07.012

Cited by 39 publications

(49 citation statements)

References 126 publications

(152 reference statements)

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“…However, the overall complement activation was lower compared to healthy volunteers. This can be considered a sign of pre-existing chronic complement activation, which is well described in HD patients [11,12,14]. Concordantly, in our in-vivo experiments, elevated C3d/C3 ratio and C5b-9 serum levels were measured in blood samples taken from these patients prior to dialysis.…”

Section: Discussionsupporting

confidence: 84%

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Hempel

Poppelaars²,

Costa

et al. 2016

Am J Nephrol

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Background: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA). Methods: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients. Results: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation. Conclusion: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

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Section: Discussionsupporting

confidence: 84%

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Hempel

Poppelaars²,

Costa

et al. 2016

Am J Nephrol

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“…Nevertheless, these networks have several common characteristics, which allow for multiple instances of cross-talk and can explain the association of both systems with several clinical inflammatory and thrombotic conditions (25 ). Furthermore, therapeutic complement C3 inhibition prevents complement activation and reduces markers of immune cell activation, inflammation, and coagulation (36 ). In the alternative pathway of complement activation, spontaneous conversion of complement C3 into C3a and C3b triggers the complement cascade (37 ).…”

Section: Discussionmentioning

confidence: 99%

Complement C3 and High Risk of Venous Thromboembolism: 80517 Individuals from the Copenhagen General Population Study

2016

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BACKGROUND Complement activation may contribute to venous thromboembolism, including deep venous thrombosis and pulmonary embolism. We tested the hypothesis that high complement C3 concentrations are associated with high risk of venous thromboembolism in the general population. METHODS We included 80 517 individuals without venous thromboembolism from the Copenhagen General Population Study recruited in 2003–2012. Plasma complement C3 concentrations were measured at baseline, and venous thromboembolism (n = 1176) was ascertained through April 2013 in nationwide registries. No individuals were lost to follow-up. RESULTS Complement C3 concentrations were approximately normally distributed, with a mean value of 1.13 g/L (interquartile range 0.98–1.26; SD 0.21). The cumulative incidence of venous thromboembolism was higher with progressively higher tertiles of complement C3 (log-rank trend: P = 3 × 10−8): at age 80, 7%, 9%, and 11% of individuals in the first, second, and third tertiles, respectively, had developed venous thromboembolism. Multivariable-adjusted hazard ratios for venous thromboembolism compared with individuals in the first tertile were 1.36 (95% CI, 1.16–1.59) for those in the second tertile and 1.58 (1.33–1.88) for those in the third tertile. Corresponding values were 1.36 (1.16–1.60) and 1.57 (1.33–1.87) after additional adjustment for C-reactive protein and 1.27 (1.09–1.49) and 1.31(1.10–1.57) after additional adjustment for body mass index. These results were similar for deep venous thrombosis and pulmonary embolism separately. The multivariable-adjusted hazard ratio for venous thromboembolism for a 1-g/L increase in complement C3 was 2.43 (1.74–3.40). CONCLUSIONS High concentrations of complement C3 were associated with high risk of venous thromboembolism in the general population.

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“…While essential, this procedure exacerbates clinical complications such as muscle wasting, endothelial and immune cell dysfunction, malnutrition, and anaemia; it also increases the risk of cardiovascular disease, which represents a major cause of mortality 23,147 .…”

Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

“…Although this effect was most obvious for older cellulose-based haemodialysis filters, modern synthetic filters with improved biocompatibility still induce substantial complement activation through all initiation pathways 3,147 . The generation of C5a during haemodialysis-induced complement activation is associated with neutrophil activation and an increase in TF expression as a primary initiator of coagulation.…”

Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

“…The generation of C5a during haemodialysis-induced complement activation is associated with neutrophil activation and an increase in TF expression as a primary initiator of coagulation. Indeed, patients on haemodialysis have an elevated risk of thrombosis and exhibit increased expression of oxidative stress markers and proinflammatory cytokines — factors that are all strongly correlated with mortality in this population 147,148 . The impact of haemodialysis-induced complement activation on overall inflammation, or even mortality, is difficult to assess given the complexity of the underlying diseases and treatments.…”

Section: Complement-mediated Kidney Diseasementioning

confidence: 99%

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Complement in disease: a defence system turning offensive

2016

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Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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Targeted complement inhibition as a promising strategy for preventing inflammatory complications in hemodialysis

Cited by 39 publications

References 126 publications

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Complement C3 and High Risk of Venous Thromboembolism: 80517 Individuals from the Copenhagen General Population Study

Complement in disease: a defence system turning offensive

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