New insight into the effects of heparinoids on complement inhibition by C1-inhibitor

Poppelaars, Felix; Damman, Jeffrey; Vrij, Edwin L de; Burgerhof, Johannes G. M.; Saye, Jo Anne; Daha, Mohamed R.; Leuvenink, Henri G. D.; Uknis, Marc E.; Seelen, Marc A.

doi:10.1111/cei.12777

Cited by 32 publications

(39 citation statements)

References 30 publications

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“…However, no complement inhibition was seen by citrate anticoagulation during HD in other studies with cellulose or synthetic membranes ( 64 – 66 ). Heparinoids are also known to prevent complement activation, although this inhibition is strictly concentration dependent ( 67 ). Although heparin has been tested extensively in HD, sadly none of these studies determined the effect on complement activation.…”

Section: Hemodialysismentioning

confidence: 99%

“…Next to inhibition of the central component C3, blockage of early complement components may be equally successful. C1-INH forms a therapeutic option, since HD leads to LP activation and C1-INH could attenuate this ( 67 ). Additionally, C1-INH also affects the coagulation and contact system, which could add to the success of this therapeutic approach.…”

Section: Hemodialysismentioning

confidence: 99%

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The Complement System in Dialysis: A Forgotten Story?

et al. 2018

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Significant advances have lead to a greater understanding of the role of the complement system within nephrology. The success of the first clinically approved complement inhibitor has created renewed appreciation of complement-targeting therapeutics. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition in renal diseases and kidney transplantation. Although, complement has been known to be activated during dialysis for over four decades, this area of research has been neglected in recent years. Despite significant progress in biocompatibility of hemodialysis (HD) membranes and peritoneal dialysis (PD) fluids, complement activation remains an undesired effect and relevant issue. Short-term effects of complement activation include promoting inflammation and coagulation. In addition, long-term complications of dialysis, such as infection, fibrosis and cardiovascular events, are linked to the complement system. These results suggest that interventions targeting the complement system in dialysis could improve biocompatibility, dialysis efficacy, and long-term outcome. Combined with the clinical availability to safely target complement in patients, the question is not if we should inhibit complement in dialysis, but when and how. The purpose of this review is to summarize previous findings and provide a comprehensive overview of the role of the complement system in both HD and PD.

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Section: Hemodialysismentioning

confidence: 99%

Section: Hemodialysismentioning

confidence: 99%

The Complement System in Dialysis: A Forgotten Story?

et al. 2018

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“…Interactions between C1INH and heparin have been reported to augment rhC1INH activity 5‐ to 11‐fold and potentiate the inhibitory effect on C1‐dependent activation of the complement cascade . The synergistic effect between rhC1INH and heparin has been previously shown to enhance inhibition of the CP, LP, and AP in human samples in a dose‐dependent fashion .…”

Section: Discussionmentioning

confidence: 98%

“…G3 donors received only continuous IV heparin infusion as described with dosing titrated to a partial thromboplastin time of 80‐120 seconds. Heparin was used to potentiate the activity of rhC1INH as described previously …”

Section: Methodsmentioning

confidence: 99%

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

Danobeitia¹,

Zens²,

Chlebeck³

et al. 2020

American Journal of Transplantation

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Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival.BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 -vehicle, G2 -rhC1INH+heparin, and G3 -heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase-associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation. 1514 | DANOBEITIA ET Al. K E Y W O R D S animal models: nonhuman primate, complement biology, delayed graft function (DGF), donors and donation: donation after brain death (DBD), immunosuppression/immune modulation, ischemia reperfusion injury (IRI), kidney transplantation/nephrology, translational research/ science 1 | INTRODUC TI ON Delayed graft function (DGF) manifests as a consequence of ischemia-reperfusion injury (IRI) and is characterized by acute kidney injury (AKI) within 7 days of transplant, requiring life-sustaining dialysis. 1 The incidence of DGF in kidney transplants from brain dead (BD) donors is approximately 26% in the United States, and this rate can reach as high as 37% in kidneys from older donors and those subjected to extended cold ischemia >36 hours. 2-4 In addition to complications related to AKI in the peritransplant period, development of DGF is an important risk factor for acute cellular rejection, antibody-mediated rejection (AMR), and reduced

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“…Rossi et al demonstrated that the C1-INH potentiation by heparin oligomers is due to binding to both C1-INH and C1s [32]. Just recently, the effects of UFH and low-molecular weight heparins (LMWHs) on CP, LP and AP activation in absence and presence of C1-INH were compared [33]. …”

Section: Introductionmentioning

confidence: 99%

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

2016

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The serpin C1 inhibitor (C1-INH) is the only regulator of classical complement activation as well as the major regulator of the contact system. Its importance is demonstrated by hereditary angioedema (HAE), a severe disease with potentially life-threatening attacks due to deficiency or dysfunction of C1-INH. C1-INH replacement is the therapy of choice in HAE. In addition, C1-INH showed to have beneficial effects in other diseases characterized by inappropriate complement and contact system activation. Due to some limitations of its clinical application, there is a need for improving the efficacy of therapeutically applied C1-INH or to enhance the activity of endogenous C1-INH. Given the known potentiating effect of heparin on C1-INH, sulfated glycans (SG) may be such candidates. The aim of this study was to characterize suitable SG by evaluating structure-activity relationships. For this, more than 40 structurally distinct SG were examined for their effects on C1-INH, C1s and FXIIa. The SG turned out to potentiate the C1s inhibition by C1-INH without any direct influence on C1s. Their potentiating activity proved to depend on their degree of sulfation, molecular mass as well as glycan structure. In contrast, the SG had no effect on the FXIIa inhibition by C1-INH, but structure-dependently modulated the activity of FXIIa. Among the tested SG, β-1,3-glucan sulfates with a Mr ≤ 10 000 were identified as most promising lead candidates for the development of a glycan-based C1-INH amplifier. In conclusion, the obtained information on structural characteristics of SG favoring C1-INH potentiation represent an useful elementary basis for the development of compounds improving the potency of C1-INH in diseases and clinical situations characterized by inappropriate activation of complement and contact system.

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New insight into the effects of heparinoids on complement inhibition by C1-inhibitor

Cited by 32 publications

References 30 publications

The Complement System in Dialysis: A Forgotten Story?

The Complement System in Dialysis: A Forgotten Story?

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation

Regulation of Complement and Contact System Activation via C1 Inhibitor Potentiation and Factor XIIa Activity Modulation by Sulfated Glycans – Structure-Activity Relationships

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