Pre-Transplant Assessment of Donor-Reactive, HLA-Specific Antibodies in Renal Transplantation: Contraindication vs. Risk

Abstract

OverviewIn renal transplantation, a positive cytotoxic crossmatch between donor cells and recipient serum is associated with early rejection or graft loss and was the driving force behind the establishment of HLA laboratories. Initially, crossmatches were performed by relatively insensitive techniques [e.g. leukoagglutination and direct complement-dependent cytotoxicity (CDC) of target cells]. A negative result justified proceeding, while a positive crossmatch was considered a contraindication to renal transplantation. However, the underlying premises driving this practice, namely that (i) all positive reactions were the result of relevant (i.e. HLA) antibodies that could lead to allograft rejection; and (ii) all negative reactions predicted long-term graft survival were known to be incorrect. From its first clinical description, the simple complementdependent assay was recognized as neither sufficiently specific nor sensitive to identify all relevant antibodies. Over time, more sensitive and specific lymphocyte crossmatch assays were developed that effectively decreased the incidence of early antibody-mediated rejection.In recent years, advances in immunosuppressive therapy have led clinicians to ask whether antibodies identified by these more sophisticated crossmatch techniques represent a contraindication to transplantation. To answer this question, it is essential to prove (or disprove) that antibodies specific for donor HLA antigens are present in recipient sera. A critical analysis of the literature revealed that the majority of studies failed to provide sufficient evidence to ensure that positive (as well as negative) crossmatches were correctly assigned. Indeed, few investigators performed the labor-intensive studies necessary to document that positive crossmatches were the result of antibodies specific for donor HLA antigens. Furthermore, the testing methodology used in those studies was relatively insensitive compared with current and emerging technologies. Given these limitations, we believe it is essential to re-examine the conclusions of studies that formed the basis of our current crossmatch paradigms.Just as the clinical application of calcineurin inhibitors revolutionized transplant medicine, the recent development of HLA antigen specific solid-phase assays (i.e., ELISA and microparticle-based flow cytometric assays) has similarly revolutionized our ability to detect HLA antibodies. Specifically, by documenting whether patient sera possess donor-reactive HLA antibodies, a lymphocyte crossmatch can now be more reliably interpreted. Indeed, with solidphase data, a positive lymphocyte crossmatch can now be categorized as (i) clinically irrelevant, (ii) a risk factor for rejection or graft loss, or (iii) a contraindication to renal transplantation. It is our position that only with accurate risk assessment can desensitization protocols [e.g., intervenous gamma globulin (IVIG) with or without plasmaphereisis] be optimally applied.

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

“…Though the risk for immune-mediated allograft injury may be recognized prior to transplantation in the form of preformed HLA class II DSA (63,70,71) and positive cross-matches (47), anti-class II DSA may also appear posttransplant (72)(73)(74)(75). Knowledge of the eplet load and the immunogenicity of particular eplets, may be used for risk stratification and inform personalized surveillance (DSA monitoring and surveillance biopsies) and therapeutic regimens.…”

Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes

“…Preformed anti-donor class II antibodies increase the risk of transplant failure [1][2][3][4][5][6][7][8][9] and the post-transplant development of anti-class II antibodies is associated with a higher incidence of acute and chronic rejection [10][11][12][13][14][15][16][17][18][19] Current class II matching strategies for kidney transplantation consider only the HLA-DR antigens controlled by the DRB1 locus but mismatching for HLA-DQ and HLA-DP may also lead to lower graft survival rates [20][21][22][23][24][25]. Newer serum screening methods such as ELISA, Flow Cytometry and Luminex have greatly enhanced the detection of anti-HLA-DQ and HLA-DP antibodies and their association with transplant rejection [2,7,[26][27][28][29].…”

Addition of Plasmapheresis Decreases the Incidence of Acute Antibody-Mediated Rejection in Sensitized Patients with Strong Donor-Specific Antibodies

“…Most studies have demonstrated that CDC T cell cross-match-negative but CDC B or FC T/B cell cross-match-positive patients with DSA are at higher risk for developing acute cellular, antibody-mediated, and chronic rejection and graft loss (9,10). The role of desensitization protocols for these patients has not been studied in a large cohort.…”