Specificity, strength, and evolution of pretransplant donor-specific HLA antibodies determine outcome after kidney transplantation

Abstract

In this cohort study (N = 924), we investigated the evolution and clinical significance of pretransplant donor-specific HLA antibodies (preDSA), detected in the singleantigen beads assay but complement-dependent cytotoxicity crossmatch-negative.Donor specificity of the preDSA (N = 107) was determined by high-resolution genotyping of donor-recipient pairs. We found that in 52% of the patients with preDSA, preDSA spontaneously resolved within the first 3 months posttransplant. PreDSA that persisted posttransplant had higher pretransplant median fluorescence intensity values and more specificity against DQ. Patients with both resolved and persistent DSA had a high incidence of histological picture of antibody-mediated rejection (ABMR h ; 54% and 59% respectively). Patients with preDSA that persisted posttransplant had worse 10-year graft survival compared to resolved DSA and preDSA-negative patients. Compared to cases without preDSA, Cox modeling revealed an increased risk of graft failure only in the patients with persistent DSA, in the presence (hazard ratio [HR] = 8.3) but also in the absence (HR = 4.3) of ABMR h . In contrast, no increased risk of graft failure was seen in patients with resolved DSA. We conclude that persistence of preDSA posttransplant has a negative impact on graft survival, beyond ABMR h . Even in the absence of antibody-targeting therapy, low median fluorescence intensity DSA and non-DQ preDSA often disappear early posttransplantation and are not deleterious for graft outcome. K E Y W O R D S alloantibody, antibody-mediated (ABMR), clinical research/practice, deceased, donors and donation, health services and outcomes research, histocompatibility, kidney transplantation/ nephrology, major histocompatibility complex (MHC), organ procurement and allocation, rejection, risk assessment/risk stratification 1 | INTRODUC TI ON With the introduction of the complement-dependent lymphocytoxicity crossmatching (CDC-XM), donor-specific antibodies (DSA) have been established as the main determinant of successful | 3101 SENEV Et al.

What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation?

“…Persistence of preformed DSA posttransplant correlates with an increased risk of ABMR and graft loss, and can occur in up to ~50% of individuals 20‐23 . Persistence correlates with initial level of DSAs, the number of preformed DSAs, and with a reported hierarchy of HLA‐DRβ 3/4/5 > HLA‐DQα 1 β 1 or HLA‐DRβ 1 > Class I 20,23 . In aggregate, the data support that alloimmune memory, in the context of preformed DSA, carries a risk for ABMR and graft loss regardless of the level of detection.…”

“…In contrast, a systematic review and meta‐analysis in both living and deceased donor recipients with a negative Flow CXM but positive SAB DSA at transplantation found an increased risk for both ABMR and graft loss 19 . Persistence of preformed DSA posttransplant correlates with an increased risk of ABMR and graft loss, and can occur in up to ~50% of individuals 20‐23 . Persistence correlates with initial level of DSAs, the number of preformed DSAs, and with a reported hierarchy of HLA‐DRβ 3/4/5 > HLA‐DQα 1 β 1 or HLA‐DRβ 1 > Class I 20,23 .…”

“…In the context of ABMR, what might a viable Phase 3 trial look like to get to full regulatory drug approval? Although de novo DSA or active ABMR is linked to poor long‐term graft outcome, not all de novo DSA or active ABMR results in graft loss 23,27,36 . Moreover, the rate of progression to graft loss is heterogenous—time to 50% post de novo DSA graft loss was longer in recipients with a subclinical onset vs a clinical onset of de novo DSA (8.3 vs 3.3 years, P < .0001) 38 .…”

The role of HLA-DP mismatches and donor specific HLA-DP antibodies in kidney transplantation: a case series

“…Another limitation of our series is the selection bias of the different cohorts, as we only included donor-recipient pairs whose HLA-DP type was known. HLA-DP typing was only routinely performed when HLA-DP antibodies were present and in the context of a large retrospective study an additional 1000 donor-patient pairs were HLA-DP typed with NGS [30]. To perform a correct HLAMatchmaker analysis, an additional criterion was that the HLA class II antibody screening was negative before transplantation.…”

Potential Novel Biomarkers in Chronic Graft-Versus-Host Disease

“…It is interesting to note that although HLA-DQ can be considered as a low-expression locus on the allograft endothelium in solid organ transplantation, it is the most frequently detected de novo DSA post-transplantation (reviewed in ( 56 ) and potential mechanisms of HLA-DQ alloantibody mediated damage to the allograft endothelium have been revealed ( 57 ). Moreover, the importance of pre-transplantation DSA anti-DQ has been recently reported to be independently associated with graft failure, and detection of DSA specific for HLA-DQ is a major predictor for graft failure ( 58 ). Analysis of DSA in HSCT is additionally complicated by the different sources of stem cells used in previous studies of HSCT, as well as different extents of HLA-loci matching.…”