Abstract
BackgroundAnti-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 findingsTo 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.ConclusionsIn 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 registrationNational Clinical Trial protocol ID: NCT03438058.
Highlights
Organ transplantation is the treatment of choice for many patients with end-stage chronic disease, which is an increasing burden on industrialized and newly industrialized countries [1,2]
We found that circulating complement-activating anti-human leukocyte antigen (HLA) donor-specific antibody (DSA) had a significant deleterious impact on solid organ transplant survival and risk of rejection
Not all antibodies are equal in terms of pathogenicity, and they exert a heterogeneous influence on organ allograft outcomes, ranging from acute forms of rejection leading to immediate allograft dysfunction and early allograft loss to more indolent or subclinical forms leading to progressive allograft deterioration
Summary
Organ transplantation is the treatment of choice for many patients with end-stage chronic disease, which is an increasing burden on industrialized and newly industrialized countries [1,2]. Greater precision in predicting allograft outcomes using a mechanistically informed, noninvasive biomarker generalizable to diverse solid organ transplants has been identified as a major goal by professional societies (e.g., the European Society of Organ Transplantation, the American Society for Transplantation, and the American Society of Transplant Surgeons), agencies (e.g., the European Medicine Agency and the Food and Drug Administration) [31], and consortia [32] These groups have pointed to the need for such biomarkers as vital both to optimizing allocation policy and to better stratifying the risk of long-term allograft failure for individual patients. This meta-analysis aims to evaluate the role of complement-activating anti-HLA DSAs on graft survival and graft rejection across the entire spectrum of solid organ transplants. Complement-activating anti-HLA antibodies and solid organ transplant survival: A meta-analysis
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