Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: A systematic review and meta-analysis

Antoine Bouquegneau, Charlotte Loheac, Olivier Aubert, Yassine Bouatou, Denis Viglietti, Jean-Philippe Empana, Camilo Ulloa, Mohammad Hassan Murad, Christophe Legendre, Denis Glotz, Annette M Jackson, Adriana Zeevi, Stephan Schaub, Jean-Luc Taupin, Elaine F Reed, John J Friedewald, Dolly B Tyan, Caner Süsal, Ron Shapiro, E Steve Woodle, Luis G Hidalgo, Jacqueline O'Leary, Robert A Montgomery, Jon Kobashigawa, Xavier Jouven, Patricia Jabre, Carmen Lefaucheur, Alexandre Loupy, Antoine Bouquegneau, Charlotte Loheac, Olivier Aubert, Yassine Bouatou, Denis Viglietti, Jean-Philippe Empana, Camilo Ulloa, Mohammad Hassan Murad, Christophe Legendre, Denis Glotz, Annette M Jackson, Adriana Zeevi, Stephan Schaub, Jean-Luc Taupin, Elaine F Reed, John J Friedewald, Dolly B Tyan, Caner Süsal, Ron Shapiro, E Steve Woodle, Luis G Hidalgo, Jacqueline O'Leary, Robert A Montgomery, Jon Kobashigawa, Xavier Jouven, Patricia Jabre, Carmen Lefaucheur, Alexandre Loupy

Abstract

Background: Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations.

Methods and findings: To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55-3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05-6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection.

Conclusions: In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification.

Trial registration: National Clinical Trial protocol ID: NCT03438058.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: AMJ declares Speaker Bureau with Honoraria for ThermoFisher-One Lambda Corporation. ThermoFisher-One Lambda Corporation is involved in the manufacture of C1q anti-HLA antibody test. JK has received research grants and/or research support from Novartis, CareDx, and TransMedics.

Figures

Fig 1. Flow chart summarizing the research…
Fig 1. Flow chart summarizing the research strategy for study identification and selection.
DSA, donor-specific antibody; SAB, single-antigen bead.
Fig 2. Funnel plot representing the analysis…
Fig 2. Funnel plot representing the analysis for publication bias with Egger’s test for bias.
Each dot represents a study; the y-axis represents study precision (95% CIs), and the x-axis shows the SE of the HR. CI, confidence interval; HR, hazard ratio; SE: standard error.
Fig 3. Association between circulating complement-activating anti-HLA…
Fig 3. Association between circulating complement-activating anti-HLA DSAs and the risk of allograft loss.
Fig 3 shows the forest plot of the association between complement-activating anti-HLA DSAs and the risk of allograft loss for each study and overall (n = 29). Studies are listed by date of publication. Number of patients are listed in the 3 cohort columns. The black diamond-shaped boxes represent the HR for each individual study. The grey boxes around the black diamond represent the weight of the study, and lines represent the 95% CI for individual studies. The blue diamond at the end represents the pooled HR. The number of patients in the overall population does not correspond to the sum of the different groups for the studies of Kaneku et al. (2012) (3 patients), Sicard et al. (2015) (4 patients), and Moktefi et al. (2017) (3 patients) either because the data for these patients were missing or because they were not involved in the analysis. CI, confidence interval; DSA, donor-specific antibody; HLA, human leukocyte antigen; HR, hazard ratio.
Fig 4. Association between complement-activating anti-HLA DSAs…
Fig 4. Association between complement-activating anti-HLA DSAs and the risk of rejection.
Fig 4 shows the forest plot of the association between complement-activating anti-HLA DSAs and the risk of rejection for each study and overall (n = 13). Studies are listed by date of publication. The black diamond-shaped boxes represent the HR for each individual study. The grey boxes around the black diamond represent the weight of the study, and lines represent the 95% CI for individual studies. The blue diamond at the end represents the overall HR. CI, confidence interval; DSA, donor-specific antibody; HLA, human leukocyte antigen; HR, hazard ratio.
Fig 5. Association of circulating complement-activating anti-HLA…
Fig 5. Association of circulating complement-activating anti-HLA DSAs with the risk of allograft loss in selected studies with multivariable models including MFI and complement-activating anti-HLA DSA.
Fig 5 shows the forest plot of the association between complement-activating anti-HLA DSAs and the risk of allograft loss in studies with multivariable models including MFI and complement-activating anti-HLA DSA (n = 8). Studies are listed by date of publication. The black diamond-shaped boxes represent the HR for each individual study. The grey boxes around the black diamond represent the weight of the study, and lines represent the 95% CI for individual studies. The blue diamond at the end represents the overall HR. The number of patients in the overall population does not correspond to the sum in the different groups for the studies of Kaneku et al. (2012) (3 patients) and Sicard et al. (2015) (4 patients) either because the data for these patients were missing or because they were not involved in the analysis. CI, confidence interval; DSA, donor-specific antibody; HLA, human leukocyte antigen; HR, hazard ratio; MFI, mean fluorescence intensity.

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