Complement-fixing donor-specific anti-HLA antibodies and kidney allograft failure

Cazarote, Helena B.; Shimakura, Sílvia Emiko; Valdameri, Joana S.; Contieri, F.; Glehn, Cristina Q.C. von; Aita, Carlos Alberto Mayora; Susin, Michelle F.; Sotomaior, Vanessa Santos; Glehn-Ponsirenas, Renata

doi:10.1016/j.trim.2018.03.002

Cited by 9 publications

(7 citation statements)

References 22 publications

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“…Although the use of the complement-fixing assays pre-transplant to identify unacceptable antigen mismatches has been reported (Chen et al, 2011;Chin et al, 2011), the majority of studies assessing the clinical relevance of complement-fixing DSA have focused on post-transplant de novo antibody production correlation with transplant outcome (Bailly et al, 2018;Bamoulid et al, 2017;Cazarote et al, 2018;Freitas et al, 2013;Guidicelli et al, 2016;Kim et al, 2018;Lan & Tinckam, 2018;Loupy et al, 2013;Pelletier et al, 2018;Thammanichanond et al, 2014;Viglietti et al, 2017). Although Malheiro et al (2017) concluded that C1q-binding ability is a better pre-transplant predictor of AMR than Luminex SAB ® positivity (Malheiro et al, 2017), several other publications have suggested that the modified LABScreen C1q assay does not offer sufficient additional clinical information pre-transplant to justify the additional laboratory costs (Gebel & Bray, 2019;Peacock et al, 2014;Taylor et al, 2017).…”

Section: Clinical Relevance Of Luminex Sab ® Modification Assaysmentioning

confidence: 99%

Approaches for the characterization of clinically relevant pre‐transplant human leucocyte antigen (HLA) antibodies in solid organ transplant patients

Rosser

Sage

2021

Int J Immunogenetics

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The introduction of new immunosuppressive drugs in the 1980s able to minimize cellular rejection enabled successful solid organ transplantation and improved graft survival rates, even where Human Leucocyte Antigen (HLA) mismatched donor organs were transplanted (Muntean & Lucan, 2013;Thurman et al., 2019). While organ allocation schemes strive to minimize HLA mismatches, it is accepted that most transplants will have some level of HLA mismatch to ensure the effective utilization of a finite resource (Montgomery et al., 2018;NHS Blood & Transplant, 2019).Although HLA mismatches are permissible in solid organ transplantation, the presence of circulating antibodies directed against mismatched donor HLA antigens at the time of transplant can initiate acute antibody-mediated rejection (AMR), leading to graft dysfunction, endothelial inflammation and potential graft loss (Stites et al., 2015). These pre-transplant donor-specific HLA antibodies (DSA) can damage the organ through the activation of the complement cascade, through antibody-dependent cell-mediated cytotoxicity (ADCC) via Natural Killer (NK) cells and/or by direct opsonization

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Section: Clinical Relevance Of Luminex Sab ® Modification Assaysmentioning

confidence: 99%

Approaches for the characterization of clinically relevant pre‐transplant human leucocyte antigen (HLA) antibodies in solid organ transplant patients

Rosser

Sage

2021

Int J Immunogenetics

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“…Complement fixing donor specific HLA antibodies have been shown to have a higher immunological risk as compared with non‐complement fixing donor specific HLA antibodies 2,4–8,13,15–17 . Without CDC crossmatching, it would not be possible to stratify this risk, as the SAB assay does not differentiate between complement and non‐complement fixing antibodies 15,18 .…”

Section: Introductionmentioning

confidence: 99%

“…1 The detection of anti-HLA antibodies is crucial for risk assessment for solid organ recipients, and in particular the is strong evidence demonstrating that complement activating HLA antibodies are more likely to be pathogenic and lead to hyperacute rejection and/or graft loss. [2][3][4][5][6][7][8][9][10][11][12] The CDC crossmatch assay, originally described by Patel and Terasaki, 13 detected complement activating HLA antibodies and was a major development in the transplantation field, preventing hyperacute rejection and also enabling successful transplantation of sensitised recipients. The standard CDC assay has remained an integral component of donor allocation for over 50 years, although is currently being phased out in favour of solid phase assays and virtual crossmatch allocation, 14 even though these solid-phase platforms do not routinely have the ability to differentiate complement activating HLA antibodies from HLA antibodies that lack complement activating function.…”

Section: Introductionmentioning

confidence: 99%

C3d‐binding assay for the detection of complement activating HLA antibodies: A useful tool for allocation to highly sensitised recipients in the post‐CDC era?

Wong

Downing

Santis

et al. 2023

HLA

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The CDC crossmatch test is being phased out in solid organ donor allocation, and standard luminex single antigen bead assays do not differentiate complement activating function of HLA antibodies. The current study investigated the LIFECODES C3d-binding assay to determine if it could accurately predict actual T and B cell CDC results in a cohort of highly sensitised patients.Nineteen serum samples from different highly sensitised solid organ patients were crossmatched against cells from 62 unique donors, with 174 total T and B cell crossmatches performed. The sera also underwent SAB assay using OLI and LC platforms, and C3d-binding assay. Complement activating ability of each unique HLA antibody specificity detected using SAB was assigned based on the actual CDC results, which was then used to determine the accuracy of the C3d-binding assay. The C3d-binding assay was found to be highly accurate, with sensitivity of 95%, specificity 89% and negative predictive value 97% for class I DSA and the T cell CDC crossmatch results. Furthermore, we found 100% accuracy for prediction of the complement activating function of HLA-C antibodies. Negative predictive value of above 90% was also found for HLA class II DSA. C3d-binding proved more accurate than virtual crossmatch alone to predict CDC results. This study confirms that the C3d-binding assay predicts actual CDC crossmatch results accurately. In particular, the high negative predictive value of the C3d-binding assay may be extremely useful to define HLA antibodies that do not activate complement in highly sensitised recipients.

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“…Donor‐reactive antibodies against HLA, both pre‐transplant and de novo, are a major cause of chronic rejection in transplant recipients. Additionally, the capability of these antibodies to independently activate the complement system increases the risk of graft loss 1,2 . This association has led to the inclusion of C4d deposition in the kidney in the diagnosis of antibody‐mediated rejection as proposed in Banff 2017 criteria 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, the capability of these antibodies to independently activate the complement system increases the risk of graft loss. 1 , 2 This association has led to the inclusion of C4d deposition in the kidney in the diagnosis of antibody‐mediated rejection as proposed in Banff 2017 criteria. 3 However, in 10%–35% of patients with antibody‐mediated rejection C4d deposition was observed without involvement of anti‐HLA antibodies, 4 , 5 suggesting that non‐HLA antibodies can bind to the kidney graft and activate complement.…”

Section: Introductionmentioning

confidence: 99%

Complement component C3 and C5b‐9 deposition on hypoxia reperfused endothelial cells by non‐HLA antibodies against RhoGDI2: A player involved in graft failure?

Kardol‐Hoefnagel

Michielsen

Ehlers

et al. 2022

HLA

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Antibodies against Rho GDP‐dissociation inhibitor 2 (RhoGDI2) are associated with inferior graft survival in transplant patients receiving a kidney from deceased donors. Although this suggests that these antibodies contribute to graft injury because of ischemia, it remains unknown whether they are also pathogenically involved in the process of graft loss. To study this, we firstly analyzed the IgG subclass profile of anti‐RhoGDI2 antibodies in kidney transplant recipients, and whether antibody titers change over time or because of acute rejection. Next, we investigated the expression of RhoGDI2 on primary kidney and lung endothelial cells (ECs) upon hypoxia reperfusion. In addition, the complement‐fixing properties of anti‐RhoGDI2 antibodies were studied using imaging flow cytometry. Anti‐RhoGDI2 antibodies in patients are mainly IgG1, and titers remained stable and seemed not be changed because of rejection. Antibodies against RhoGDI2, which surface expression seemed to increase upon hypoxia reperfusion, co‐localized with C3 on ECs. Binding of human IgG1 monoclonal anti‐RhoGDI2 antibodies as well as patient derived antibodies, resulted in complement activation, suggesting that these antibodies are complement fixing. This study suggested a potential pathogenic role of anti‐RhoGDI2 antibodies in kidney graft loss. During ischemia reperfusion, the ability of these antibodies to fix complement could be one of the mechanisms resulting in tissue injury.

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Complement-fixing donor-specific anti-HLA antibodies and kidney allograft failure

Cited by 9 publications

References 22 publications

Approaches for the characterization of clinically relevant pre‐transplant human leucocyte antigen (HLA) antibodies in solid organ transplant patients

Approaches for the characterization of clinically relevant pre‐transplant human leucocyte antigen (HLA) antibodies in solid organ transplant patients

C3d‐binding assay for the detection of complement activating HLA antibodies: A useful tool for allocation to highly sensitised recipients in the post‐CDC era?

Complement component C3 and C5b‐9 deposition on hypoxia reperfused endothelial cells by non‐HLA antibodies against RhoGDI2: A player involved in graft failure?

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