The Pre-Transplant Non-HLA Antibody Burden Associates With the Development of Histology of Antibody-Mediated Rejection After Kidney Transplantation

Abstract

BackgroundMany kidney allografts fail due to the occurrence of antibody-mediated rejection (ABMR), related to donor-specific anti-HLA antibodies (HLA-DSA). However, the histology of ABMR can also be observed in patients without HLA-DSA. While some non-HLA antibodies have been related to the histology of ABMR, it is not well known to what extent they contribute to kidney allograft injury. Here we aimed to investigate the role of 82 different non-HLA antibodies in the occurrence of histology of ABMR after kidney transplantation.MethodsWe included all patients who underwent kidney transplantation between 2004-2013 in a single center and had biobanked serum. Pre- and post-transplant sera (n=2870) were retrospectively tested for the presence of 82 different non-HLA antibodies using a prototype bead assay on Luminex (Immucor, Inc). A ratio was calculated between the measured MFI value and the cut-off MFI defined by the vendor for each non-HLA target.Results874 patients had available pretransplant sera and were included in this analysis. Of them, 133 (15.2%) received a repeat kidney allograft, and 100 (11.4%) had pretransplant HLA-DSA. In total, 204 (23.3%) patients developed histology of ABMR after kidney transplantation. In 79 patients (38.7%) the histology of ABMR was explained by pretransplant or de novo HLA-DSA. The multivariable Cox analysis revealed that only the broadly non-HLA sensitized (number of positive non-HLA antibodies) patients and those with the highest total strength of the non-HLA antibodies (total ratios of the positive non-HLA antibodies) were independently associated with increased rates of histology of ABMR after transplantation. Additionally, independent associations were found for antibodies against TUBB (HR=2.40; 95% CI 1.37 – 4.21, p=0.002), Collagen III (HR=1.67; 95% CI 1.08 – 2.58, p=0.02), VCL (HR=2.04; 95% CI 1.12 – 3.71, p=0.02) and STAT6 (HR=1.47; 95% CI 1.01 – 2.15, p=0.04). The overall posttransplant non-HLA autoreactivity was not associated with increased rates of ABMRh.ConclusionsThis study shows that patients highly and broadly sensitized against non-HLA targets are associated with an increased risk of ABMR histology after kidney transplantations in the absence of HLA-DSA. Also, some pretransplant non‐HLA autoantibodies are individually associated with increased rates of ABMR histology. However, whether these associations are clinically relevant and represent causality, warrants further studies.

Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report

“…Additional assays to detect non-HLA antibody targets are available on the Luminex platform from commercial vendors 38,[52][53][54][55][56][57] or as laboratory developed reagents. 11,12,47,56,58,59 Initial reports proposed that non-HLA antibodies are significantly associated with early T-cell-mediated rejection (TCMR), 38,52 humoral rejection, 54,55,57 and graft loss. 12,53,58 Others reported a potential synergistic nature of non-HLA antibodies with HLA-DSAs when present.…”

“…One large (n ¼ 874) study that included protocol biopsies and routine HLA DSA monitoring (3 months and annually thereafter) reported an independent association between pretransplant non-HLA antibody breadth and/or strength with features of ABMR. 57 Nevertheless, it remains unclear if non-HLA Luminex detection panels identify antibodies that mechanistically contribute to graft injury and rejection or arise from other graft injury/inflammation processes that are not caused by the non-HLA antibodies (including infection, ischemic injury, or de novo/recurrent disease).…”

Anti-glutathione S-transferase theta 1 antibodies correlate with graft loss in non-sensitized pediatric kidney recipients

“…Accordingly, a multiarray approach testing Abs directed to a wide number of potential non-HLA antigens will improve the diagnostic potential for ABMR and graft loss risk stratification ( 23 , 27 ), particularly if carried out at both serum and intragraft level, as suggested by our preliminary study. In addition to their diagnostic potential, these tools may also help gain insight into the hypothesis of an Ab burden effect on graft damage ( 32 ).…”

The Clinical Utility of Post-Transplant Monitoring of Donor-Specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report With Guideline Statements for Clinical Practice

“…Conflicting studies also exist in regards to IgG subclass differentiation [ 55 , 113 ]. The role of non-HLA post-transplant does not seem to be impactful, but the number of studies is currently limited [ 114 ].…”