Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients

Poppelaars, Felix; Costa, Mariana Gaya da; Berger, Stefan P.; Assa, Solmaz; Meter-Arkema, Anita; Daha, Mohamed R.; Son, Willem J. van; Franssen, Casper F. M.; Seelen, Marc A.

doi:10.1186/s12967-016-0995-5

Cited by 28 publications

(49 citation statements)

References 49 publications

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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: 85%

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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: 85%

“…The ELISA for C1q, C3d, C3 mannose-binding lectin (MBL), properdin, and C5b-9 were performed as described previously [10,11,12]. …”

Section: Methodsmentioning

confidence: 99%

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Hempel

Poppelaars²,

Costa

et al. 2016

Am J Nephrol

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“…Similar findings were reported in a different tandem mass spectrometry on eluates and serum samples of five patients during the hemodialysis session: the eluate intensity of ficolin-2, clusterin, complement C3c fragment, and apolipoprotein A1 differed significantly from the counterpart serum levels, implying preferential adsorption to the polysulfone dialyzers [27]. The reduction of such factors in bloodstream was associated with a serum increase of C5a and leukopenia during hemodialysis, and a higher incidence of cardiovascular events was found in patients with lower serum levels of mannose binding leptin (MBL) [29,30]. Notably, this relationship was not correlated with other traditional cardiovascular risk factors (Table 1) [30].…”

Section: Complement Systemmentioning

confidence: 95%

Immunological Effects of a Single Hemodialysis Treatment

et al. 2020

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Immune disorders, involving both innate and adaptive response, are common in patients with end-stage renal disease under chronic hemodialysis. Endogenous and exogenous factors, such as uremic toxins and the extracorporeal treatment itself, alter the immune balance, leading to chronic inflammation and higher risk of cardiovascular events. Several studies have previously described the immune effects of chronic hemodialysis and the possibility to modulate inflammation through more biocompatible dialyzers and innovative techniques. On the other hand, very limited data are available on the possible immunological effects of a single hemodialysis treatment. In spite of the lacking information about the immunological reactivity related to a single session, there is evidence to indicate that mediators of innate and adaptive response, above all complement cascade and T cells, are implicated in immune system modulation during hemodialysis treatment. Expanding our understanding of these modulations represents a necessary basis to develop pro-tolerogenic strategies in specific conditions, like hemodialysis in septic patients or the last session prior to kidney transplant in candidates for receiving a graft.

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“…In dialysis, complement activation is mainly caused by the interaction of blood with the HD membrane ( 4 ). Regardless of the efforts to improve biocompatibility, complement activation still occurs in HD, even with modern membranes ( 8 – 10 ). It has been hypothesized that complement activation leads to HD-induced inflammation and thereby increases the subsequent cardiovascular risk ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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-α 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-α 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-α 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.

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Strong predictive value of mannose-binding lectin levels for cardiovascular risk of hemodialysis patients

Cited by 28 publications

References 49 publications

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations

Immunological Effects of a Single Hemodialysis Treatment

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

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