Clinical relevance of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter?

Anti-HLA donor-specific antibodies (DSA) identified by single antigen bead array (SAB) are questioned for their excess in sensitivity and lack of event prediction after transplantation. We retrospectively evaluated specific types of preformed DSA (class I, class II or C1q-fixing) and their impact on graft survival. Kidney transplantations performed across negative CDC-crossmatch were included (n=355). Anti-HLA antibodies were tested using SAB to identify DSA and their capacity to fix C1q. Twenty-eight patients with pretransplant DSA(+) with MFI>2000 were selected to assess C1q fixation. DSA were C1q+ in 15 patients and C1q- in 13, without significant differences in demographics, acute rejection, graft loss or renal function. The maximum MFI of DSA in patients with C1q-fixing DSA was significantly higher (p=0.008). Patients with DSA class-I suffered more antibody-mediated rejection (AMR) and had worse graft survival than class-II. The capacity of DSA I to fix C1q did not correlate with rejection, graft function or graft loss. C1q testing in pretransplant sera with DSA was unable to predict acute antibody-mediated rejection or early graft loss, but the presence of DSA class I compared to DSA only class II did. Despite non-fixing complement in vitro, pretransplant C1q-negative DSA I can mediate rejection and graft loss.

Crespo M ，Torio A ，Mas V ，Redondo D ，Pérez-Sáez MJ ，Mir M ，Faura A ，Guerra R ，Montes-Ares O ，Checa MD ，Pascual J ... -  《-》

C1q Binding Activity of De Novo Donor-specific HLA Antibodies in Renal Transplant Recipients With and Without Antibody-mediated Rejection.

Yell M ，Muth BL ，Kaufman DB ，Djamali A ，Ellis TM ... -  《-》

Determining donor-specific antibody C1q-binding ability improves the prediction of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation.

Detrimental impact of preformed donor-specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody-mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney-transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti-HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q-binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q-binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q- high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q-binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q-binding ability was a better predictor of AMR and correlated with graft survival, C1q-SAB may be a particularly useful tool.

Malheiro J ，Tafulo S ，Dias L ，Martins S ，Fonseca I ，Beirão I ，Castro-Henriques A ，Cabrita A ... -  《-》

Impact of alloantibody strength in crossmatch negative DSA positive kidney transplantation.

The clinical relevance of pre-transplant "low-level" donor specific anti-HLA antibodies (DSAs) in crossmatch negative kidney transplant recipients remains unclear. To determine what level of DSA associates with antibody mediated rejection (AMR) could be the way to measure the clinical relevance of pre-transplant "low-level" donor specific anti-HLA antibodies (DSAs) in crossmatch negative kidney transplant recipients. A retrospective analysis of 221 patients from October 2008 to December 2009 was included in this study. Sera were obtained pre-transplant and two weeks post-transplant and tested for DSA using LABScreen single antigen beads. Among the 221 patients, 11 experienced AMR within 200days after transplant (5%). Pre-transplant DSA was associated with AMR at multiple mean fluorescence intensity (MFI) cutoffs (500, 1000, 2000, 3000, 5000; p=0.003, 0.001, 0.007, 0.003, and 0.003, respectively). No correlation was seen between acute T-cell mediated rejection (CMR) and pre-transplant DSA at any of the same MFI cutoffs. There was an increased risk of AMR with higher levels of pre-transplant DSA. Finally, an increase in DSA MFI from pre- to two weeks post-transplant was indicative of a higher probability of AMR. Overall, this data supports using the single antigen bead to detect "low-level" DSA both pre- and post- as having a positive and persistent DSA may be predictive of higher AMR rates and poorer graft survival.

Wu P ，Jin J ，Everly MJ ，Lin C ，Terasaki PI ，Chen J ... -  《-》

Analysis of preformed donor-specific anti-HLA antibodies characteristics for prediction of antibody-mediated rejection in kidney transplantation.

The relevance of preformed donor specific antibodies (DSA) detected by Luminex assays, with a negative complement-dependent cytotoxicity (CDC) crossmatch, remains unsettled in kidney transplantation (KT). We aimed to analyze the impact of preformed DSA characteristics on kidney graft outcomes. In 462 patients that received a kidney graft in our unit, between 2007 and 2012, pre-transplant sera were analyzed by Luminex screening assay to determine the presence of anti-human leukocyte antigen (HLA) antibodies and single-antigen bead assay [positive if mean fluorescence intensity (MFI) ≥ 1000] to assign anti-HLA specificities. Anti-HLA antibodies were present in 95 patients (20.6%), but only 40 (8.7%) had DSA. Antibody-mediated rejection (AMR) at 1-year was higher in patients with DSA (35.0%) than in those without them (0.9%) (P < 0.001). Only DSA with a MFI of >3000 were significantly associated with AMR occurrence. Receiver operator curves revealed that a MFI of >4900 in the highest DSA bead had a high sensitivity (85.7%) and that the sum of all DSA beads MFI > 11,000 had a high specificity (92.3%) for AMR prediction. Anti-thymocyte globulin versus basiliximab induction was more frequent in DSA+ AMR- (65.4%) versus DSA+ AMR+ (34.6%) patients (P = 0.072). Five-year censored graft survival was lower in DSA+ than in DSA- patients (respectively, 84.8% versus 94.9%, P = 0.006), although survival was only reduced in DSA+ AMR+ (68.8%) versus DSA+ AMR- (96.0%) patients (P = 0.038). Preformed DSA is associated with kidney graft loss, in relation with AMR occurrence. DSA strength may be used to improve immunological risk stratification of sensitized patients and their clinical management.

Malheiro J ，Tafulo S ，Dias L ，Martins LS ，Fonseca I ，Beirão I ，Castro-Henriques A ，Cabrita A ... -  《-》