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 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.

A major hurdle to improving clinical care in the field of kidney transplantation is the lack of biomarkers of the response to antibody-mediated rejection (ABMR) treatment. To discover these we investigated the value of complement-binding donor-specific anti-HLA antibodies(DSAs) for evaluating the response to treatment. The study encompassed a prospective cohort of 139 kidney recipients with ABMR receiving the standard of care treatment, including plasma exchange, intravenous immunoglobulin and rituximab. Patients were systematically assessed at the time of diagnosis and three months after treatment initiation for clinical and allograft histological characteristics and anti-HLA DSAs, including their C1q-binding ability. After adjusting for clinical and histological parameters, post-treatment C1q-binding anti-HLA DSA was an independent and significant determinant of allograft loss (adjusted hazard ratio 2.57 (95% confidence interval 1.29-5.12). In 101 patients without post-treatment C1q-binding anti-HLA DSA there was a significantly improved glomerular filtration rate with significantly reduced glomerulitis, peritubular capillaritis, interstitial inflammation, tubulitis, C4d deposition, and endarteritis compared with 38 patients with posttreatment C1q-binding anti-HLA DSA. A conditional inference tree model identified five prognostic groups at the time of post-treatment evaluation based on glomerular filtration rate, presence of cg lesion and C1q-binding anti-HLA DSA (cross-validated accuracy: 0.77). Thus, circulating complement-binding anti-HLA DSAs are strong and independent predictors of allograft outcome after standard of care treatment in kidney recipients with ABMR.