Are All Donor-Specific Antibodies Detected by Solid-Phase Assay Before Transplantation Clinically Relevant? (2009)

Because new technologies based on solid-phase assays (SPA) have been routinely used in the transplant immunology laboratory, the presence of pretransplant donor-specific antibodies (DSA) against human leukocyte antigens (HLA) has generally been considered as a risk factor for antibody-mediated rejection (1). To investigate the clinical relevance of pretransplant DSA, we studied 114 kidney transplant recipients who had negative prospective T- and B-cell complement dependent cytotoxicity crossmatches at the time of transplant. We retrospectively screened pretransplant sera for circulating anti-HLA antibody and DSA on serum samples, which were taken immediately before transplantation, by using sensitive and HLA-specific Luminex assay (Labscreen single antigen; One Lambda, Canoga Park, CA). The cutoff value of the assay was 500 mean fluorescence intensity (MFI). The Luminex results did not influence transplant management (retrospective study). We found that approximately half of our patient population (55/114, 48.2%) had circulating anti-HLA antibody pretransplant (11/114, 9.6%, were DSA). Of 11 biopsy-proven acute rejection episodes posttransplant, only two had pretransplant DSA, of whom one had acute humoral rejection (C4d positive). Conversely, 9 from 11 recipients had pretransplant DSA without any posttransplant rejections episodes within 1 year after transplantation. Biopsies were not performed in these nine patients because they had normal graft function (mean glomerular filtration rate: 57±7 mL/min/1.73 m2 and a mean level of creatinine at 116±19 μmol/L) with no significant proteinuria (<0.5 g/24 hr). Therefore, if we would have taken into consideration the presence of pretransplant DSA as an absolute contraindication to transplant, 8% (9/114) of the studied patients would not have received a kidney transplant. Recently, Akalin et al. (2) reported in an analysis of 35 kidney transplant recipients with pretransplantation DSA that the addition of plasmapheresis to high-dose intravenous Ig decreased the incidence of acute rejection. The original point of this study was to stratify kidney transplant recipients according to the mean fluorescence indices of Luminex (MFI), a measure which may reflect the amount of circulating antibodies (3). Their results indicated that patients with “strong DSA” were at higher risk for developing acute humoral rejection and needed more intensive desensitization protocols. By reviewing our own data, the DSA-MFI values of the two kidney transplant patients with acute rejection were at 1004 (patient 1: anti-DR11), and 1008 and 2659 (patient 2: anti-A26 and anti-A11, respectively), that is, values relatively low according to the proposed stratification of Akalin et al. On the other hand, the pretransplant DSA-MFI values of the nine kidney transplant recipients without any rejection episodes range from 694 to 5717 (mean 2758±1398). Thus, only on the basis of these pretransplant DSA-MFI values, we could not have predicted the posttransplant acute rejection episodes. Altogether, these data confirm the high sensitivity of SPA of the Luminex type to detect circulating DSA antibodies. However, they also suggest that the positive predictive value of low-levels pretransplant DSA (e.g., MFI <6000) remains incompletely understood, and more studies are needed to define which pretransplant DSA are pathogenic posttransplant. In summary, detecting DSA pretransplant by using new SPA will likely become useful in the near future, in particular for retransplant or sensitized recipients at risk for allograft rejection, as it is the case in experience of Akalin et al. and others. Currently, it is also being used to detect and monitor posttransplant de novo DSA production. Overall, the high sensitivity of SPA brings new knowledge to the field of solid organ transplantation, which is valuable but complex. More work, therefore, should continue to be performed to better delineate the precise clinical significance of detecting circulating DSA before and after transplantation, to fully validate the routine implementation of these new techniques. Vincent Aubert Division of Immunology and Allergy Department of Medicine Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland Jean-Pierre Venetz Department of Surgery Transplantation Center Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland Giuseppe Pantaleo Division of Immunology and Allergy Department of Medicine Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland Manuel Pascual Department of Surgery Transplantation Center Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland