C3d-binding Donor-specific HLA Antibody Is Associated With a High Risk of Antibody-mediated Rejection and Graft Loss in Stable Kidney Transplant Recipients: A Single-center Cohort Study

Lee, D.R.; Kim, B.C.; Kim, J.P.; Kim, I.G.; Jeon, Mi Young

doi:10.1016/j.transproceed.2018.06.037

Cited by 7 publications

(8 citation statements)

References 31 publications

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“…As a diagnostic method, it is necessary for AMR control to establish a humoral immune monitoring method to evaluate AMR pathology in more detail and predict the development of AMR before antibodies, which induce AMR development, are detected in the serum (71,72). In addition, it has been reported that the antigen specificity of the progenitor cells of LLPCs can be determined using an in vitro assay system (22)(23)(24)(25)(26)(27), but there are no unambiguous criteria for predicting whether antibodies against donor-specific HLA antigens cause humoral immunitymediated injury in transplanted grafts (73)(74)(75). It is therefore necessary to develop a method that evaluates the reactivity of the antibody to transplanted grafts.…”

Section: Challenges Of Conventional Amr Controlmentioning

confidence: 99%

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Matsuda¹,

Watanabe²,

Li³

2021

Front. Immunol.

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Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.

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Section: Challenges Of Conventional Amr Controlmentioning

confidence: 99%

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Matsuda¹,

Watanabe²,

Li³

2021

Front. Immunol.

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“…Thus, a common thread in these studies is that the combination of pre‐ and postrenal transplantation testing for complement‐activating DSA can be of predictive value, and their use, particularly in immunologically high‐risk cases, is becoming compelling. Which measure of in vivo complement‐activating potential, C1q binding or C3d generation is superior, if at all, remains to be proven; the study by Kim et al and Lee et al [24,48] suggests the latter. Each assay measures different DSA properties; C1q binding being dependant on Fc density on the antibody target, while C3d generation quantifies the full activation potential of the DSA (including Fc cross‐linking).…”

Section: Discussionmentioning

confidence: 99%

“…Limited number of studies have looked at the HLA class of complement‐activating DSAs, and majority of these studies are limited by relatively low numbers of patients. In a recent study, de novo class II C3d‐positive DSAs were associated with higher rejection episodes and significantly lower graft survival [24]. A study that looked at the effect of C4d‐positive DSA class on ABMR found no significant difference [43].…”

Section: Discussionmentioning

confidence: 99%

“…Anti‐HLA subclasses IgG1 and IgG3 strongly activate complement and have the potential to serve as predictors of rejection and allograft survival [19‐21]. The field of antibody testing has evolved, and it is possible to study the complement proteins and split products on solid‐phase assays using isolated HLA proteins [22‐24]. The advancements in immune monitoring emphasize the need to investigate the role of DSA that activates the complement cascade in the highly sensitized patients with positive cross‐match, both pretreatment and following early transplantation.…”

Section: Introductionmentioning

confidence: 99%

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C3d‐positive donor‐specific antibodies have a role in pretransplant risk stratification of cross‐match‐positive HLA‐incompatible renal transplantation: United Kingdom multicentre study

Babu

Khovanova

Shaw³

et al. 2020

Transpl Int

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Anti‐HLA‐antibody characteristics aid to risk‐stratify patients and improve long‐term renal graft outcomes. Complement activation by donor‐specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross‐match‐positive). We explored the role of C3d‐positive DSAs in sub‐stratification of cross‐match‐positive cases and relate to the graft outcomes. We investigated 139 cross‐match‐positive living‐donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post‐transplant. C3d‐positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post‐transplant. Median follow‐up of patients was 48 months (IQR 20.47–77.57). In the multivariable analysis, pretreatment C3d‐positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37–7.86). The relative risk of death‐censored five‐year graft failure was 2.83 (95% CI 1.56–5.13). Patients with both pretreatment and Day 14 C3d‐positive DSAs had the worst five‐year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d‐negative DSA patients with the relative risk of death‐censored five‐year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub‐stratify the risk of poor graft outcome in cross‐match‐positive living‐donor renal transplantation.

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“…However, the clinical relevance of all the detected DSAs remains unclear because the presence of DSAs does not always correlate with complement-mediated cytotoxicity crossmatching and may not induce AMR. Recently, C1q-and C3d-binding assays were introduced as methods for predicting the presence of complement-binding functional antibodies; however, the prognostic value of these tests remains controversial [2][3][4][5][6][7][8]. In particular, the clinical significance of preformed DSAs (pDSAs) with complement-binding activities has been not fully evaluated.…”

Section: Introductionmentioning

confidence: 99%

C3d-Positive Preformed DSAs Tend to Persist and Result in a Higher Risk of AMR after Kidney Transplants

Choi

Lee

Park

et al. 2020

JCM

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C3d-binding assays have been introduced as methods for the prediction of the presence of complement-binding functional antibodies; however, the prognostic value of C3d-positive preformed donor-specific antibodies (pDSAs) has not been fully evaluated. In this study, we performed a retrospective investigation of the association of pDSAs and their C3d-binding capacity with one-year clinical outcomes. pDSAs were defined as donor-specific antibodies (DSAs) that were produced before kidney transplants (KTs) (pre-pDSAs) or within the first four weeks after KTs, owing to rebound immune response (post-pDSAs). Of 455 adult KT recipients, pre-pDSAs and post-pDSAs were found in 56 (12.3%) and 56 (12.3%) recipients, respectively, and C3d-positive post-pDSAs were found in 13 recipients (2.9%) in total. Approximately half of the C3d-negative pre-pDSAs (37/73, 50.7%) disappeared after transplantation; however, all C3d-positive pre-pDSAs (8/8, 100%) persisted after transplantation despite desensitization (p = 0.008). C3d-positive pDSAs were significantly associated with a higher incidence and risk of AMR (p < 0.001, OR 94.467–188.934). Identification of the C3d-binding activity of pDSAs before and early after KT is important for predicting the persistence of pDSAs and the risk of AMR induced by the presence of pDSAs.

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C3d-binding Donor-specific HLA Antibody Is Associated With a High Risk of Antibody-mediated Rejection and Graft Loss in Stable Kidney Transplant Recipients: A Single-center Cohort Study

Cited by 7 publications

References 31 publications

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

C3d‐positive donor‐specific antibodies have a role in pretransplant risk stratification of cross‐match‐positive HLA‐incompatible renal transplantation: United Kingdom multicentre study

C3d-Positive Preformed DSAs Tend to Persist and Result in a Higher Risk of AMR after Kidney Transplants

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