Characteristics of Circulating Donor Human Leukocyte Antigen-specific Immunoglobulin G Antibodies Predictive of Acute Antibody-mediated Rejection and Kidney Allograft Failure

Abstract

Background Characteristics of pretransplant antibodies directed at donor HLA (DSA) associated with adverse outcomes in kidney transplant recipients are being elucidated but uncertainties exist. Methods Prospectively screening of pretransplant sera from 543 kidney recipients using single antigen bead assays identified 154 recipients with DSA and 389 without. We investigated the association of DSA features to acute rejection (AR) and graft failure. Results One-year AR incidence was higher in DSA positive group (P<0.001), primarily due to antibody mediated rejection (AMR, 13% vs. 1.8%, P<0.001) and not T-cell mediated rejection (ACR, 5% vs.6%, P=0.65). Risk of AMR increased progressively with a rise in DSA MFI-Sum (P<0.0001). Both DSA MFI-Sum ≥6000 (OR=18; 95%CI, 7.0 to 47; P<0.001) and DSA specificity, presence of DSA against both HLA class I and II (OR=39; 95%CI, 14 to 106; P<0.0001), predicted one-year AMR, independent of other covariates. In a combined model, DSA specificity predicted AMR, independent of DSA MFI-Sum. In multivariable Cox proportional hazards models, the covariate-adjusted hazard ratio for graft failure was 2.03 (95%CI, 1.05 to 3.92; P=0.04) for DSA MFI-Sum≥6000 and 2.23 (95% CI, 1.04 to 4.80; P=0.04) for class I and II DSA. Prediction of graft loss was not independent of AMR. Conclusions Our study supports the hypothesis that characterization of pretransplant DSA, specifically presence of DSA against both HLA class I and II and the strength, as quantified by DSA MFI-Sum, is useful to estimate AMR and graft failure risk in kidney graft recipients. Elevated risk of graft failure is attributable to increased risk of AMR.

Impact of pretransplant donor‐specific antibodies on kidney allograft recipients with negative flow cytometry cross‐matches

“…Many studies show that the risk of AR is higher in patients with than without pretransplant DSA, primarily due to ABMR . The 1‐year incidence of ABMR observed in the present study (11.1%) was comparable to those observed in recent studies, with ABMR in sensitized patients usually occurring within the first year after transplant .…”

“…The presence of class I and II DSA and multiple HLA antigens did not increase the ABMR rate after KT in the present study. These findings differ from those of previous reports, which found that the presence of both class I and II DSA significantly increased the immunological risk . The relationship between AR risk and DSA classes in the present study was in agreement with results showing that the 1‐year AR rates in groups positive for class I, class II, and classes I and II were 9.9%, 22.0%, and 19.4%, respectively ( P = .10) .…”

“…Multivariate regression analysis revealed that class II DSA MFI ≥3000 was an independent predictor of ABMR, whereas class I DSA MFI ≥5000 was not significantly associated with AR or ABMR. MFI cutoff values reported a significant range from 3000‐10 000 . The study most similar to ours suggested that maximum MFI ≥3000 was associated with increased risk of AR, but that study did not separately analyze class II MFI strength .…”

“…By contrast, ABMR in sensitized patients is primarily driven by either an anamnestic response or the DSA present at KT . ABMR is recognized as one of the most prominent risk factors for graft failure . However, GS in our DSA‐positive and ‐negative groups did not differ, because early AR responded well to treatment, such as rituximab, PP, and IVIG.…”

Interpreting Anti-HLA Antibody Testing Data

“…Several groups have reported outcomes based on the immunodominant (highest MFI) at the time of transplantation (54, 55), but this approach is complicated because a DSA that appears immunodominant pretransplant may not be immunodominant posttransplant. Other groups have correlated the MFI sum with long term outcomes (52, 56). That approach is also problematic because the SAB is only semi-quantitative.…”