Preexisting Donor-Specific HLA Antibodies Predict Outcome in Kidney Transplantation

Abstract

The clinical importance of preexisting HLA antibodies at the time of transplantation, identified by contemporary techniques, is not well understood. We conducted an observational study analyzing the association between preexisting donor-specific HLA antibodies (HLA-DSA) and incidence of acute antibody-mediated rejection (AMR) and survival of patients and grafts among 402 consecutive deceaseddonor kidney transplant recipients. We detected HLA-DSA using Luminex single-antigen assays on the peak reactive and current sera. All patients had a negative lymphocytotoxic cross-match test on the day of transplantation. We found that 8-year graft survival was significantly worse (61%) among patients with preexisting HLA-DSA compared with both sensitized patients without HLA-DSA (93%) and nonsensitized patients (84%). Peak HLA-DSA Luminex mean fluorescence intensity (MFI) predicted AMR better than current HLA-DSA MFI (P ϭ 0.028). As MFI of the highest ranked HLA-DSA detected on peak serum increased, graft survival decreased and the relative risk for AMR increased: Patients with MFI Ͼ6000 had Ͼ100-fold higher risk for AMR than patients with MFI Ͻ465 (relative risk 113; 95% confidence interval 31 to 414). The presence of HLA-DSA did not associate with patient survival. In conclusion, the risk for both AMR and graft loss directly correlates with peak HLA-DSA strength. Quantification of HLA antibodies allows stratification of immunologic risk, which should help guide selection of acceptable grafts for sensitized patients.

Urinary C-X-C Motif Chemokine 10 Independently Improves the Noninvasive Diagnosis of Antibody–Mediated Kidney Allograft Rejection

“…23 Beads showing a normalized MFI.500 were considered positive. For each patient, we recorded the number, class, specificity, and MFI of all DSAs.…”

Eculizumab to Treat Antibody-Mediated Rejection in a 7-Year-Old Kidney Transplant Recipient

“…12,13 Moreover, Burns et al 14 found that in acute ABMR with positive pretransplant B-cell FCXM, complement activation within the allograft, as indicated by C4d deposition in peritubular capillaries, was related to DSA levels. These data confirm that the main pathophysiological mechanism of acute ABMR occurring early after transplant is related to the presence of high levels of DSAs, which result in the local activation of the classic complement pathway.…”

HLA Antibody Detection With Solid Phase Assays: Great Expectations or Expectations Too Great?

“…Studies from numerous investigators reported of AMR and/or graft loss in patients who's donor-specific antibody (DSA) were undetectable by complement dependent cytotoxicity assays but present by multiplex solid phase assays (36)(37)(38)(39)(40). Thus, the preferred donor lacks the HLA antigen(s) corresponding to antibodies identified by solid phase technology.…”

“…There are at least three approaches: (i) Statistical; establishing a fluorescence level (cutoff) significantly above background; (ii) Practical; correlating with a crossmatch result and (iii) Clinical; identifying a level that predicts immediate/early graft loss. Previous studies have reported correlations between MFI levels of donor-specific HLA antibodies and either clinical outcome (40,47) or crossmatch results (54), leading to the reasonable expectation that a threshold level of fluorescence can be established above which an antibody can be considered as present and below which, absent. Unfortunately, it is not that simple and straightforward.…”