The Acceptable Mismatch Program as a Fast Tool for Highly Sensitized Patients Awaiting a Cadaveric Kidney Transplantation: Short Waiting Time and Excellent Graft Outcome

Abstract

There are many highly sensitized patients on the kidney waiting lists of organ exchange organizations because it is difficult to find a crossmatch negative cadaver kidney for these patients. Recently, several protocols have been developed to remove the donor-specific human leukocyte antigen (HLA) antibodies from the serum of these patients before transplantation. These approaches, including the use of intravenous immunoglobulins, plasmapheresis and immunoglobulins (plasmapheresis-cytomegalovirus-immunoglobulin), and immunoabsorption, seem to lead to a certain success rate, although the additional immunosuppression necessary to remove and control the production of donor-specific alloantibodies may have its impact on the short-term (infections) and long-term (incidence of cancer) immune surveillance. Furthermore, some of these therapies represent a considerable financial burden for patients and society. In the present report, we advocate selection of crossmatch negative donors on the basis of the Acceptable Mismatch Program, as the first and best option for highly sensitized patients to undergo transplantations. No additional immunosuppression is necessary, and graft survival in this group of "difficult" patients is identical to that of nonsensitized recipients. Because the nature of the HLA polymorphism does not allow all patients to profit from this approach, removal of circulating HLA antibodies can be considered as a rescue therapy for those patients for whom the Acceptable Mismatch Program does not give a solution.

A Structurally Based Approach to Determine HLA Compatibility at the Humoral Immune Level

“…Exposure to mismatched X will not lead to PQR-specific antibodies in recipients who type for Y or Z. This concept has been verified by observations that highly sensitized patients do not have antibodies against intralocus and interlocus triplet matches [7,10,11,15]. On the other hand, PQR can be immunogenic for a recipient who does not type for X, Y or Z. Anti-PQR antibodies will react with the immunizing X and also with Y and Z but there might be exceptions for two reasons.…”

“…Several reports have described a conformational effect of hidden residues on HLA epitope reactivity with antibody [78,83,84,85,86]. This scenario would only apply to epitope antigenicity but not immunogenicity because highly sensitized patients do not produce antibodies to self-epitopes expressed on mismatched HLA antigens [7,10,11,15].…”

“…The patient's HLA phenotype represents the repertoire of self-triplets and HLAMatchmaker determines for each mismatched HLA antigen, which triplets in corresponding sequence positions are different. HLAMatchmaker-based matching improves transplant outcome [2][3][4][5][6], and is useful in serum analysis and the identification of acceptable mismatches for alloimmunized kidney transplant candidates [7][8][9][10][11][12][13][14][15][16] and refractory thrombocytopenic patients requiring matched platelet transfusions [17,18] The original version of HLAMatchmaker considers triplets, i.e. linear sequences of three residues at least one of which would be polymorphic [1].…”

Characteristics, Detection, and Clinical Relevance of Alloantibodies in Kidney Transplantation

“…Secondly, alloantibodies can be produced only against non-self mismatched triplets. Subsequent clinical studies have proven the validity of the HLAMatchmaker algorithm as a method for finding cross-match compatible donors for TCs with PRA values above 80% Claas et al 2004;Doxiadis et al 2005;Duquesnoy 2007Duquesnoy , 2008aDuquesnoy , 2008bLobashevsky et al, 2002). Furthermore, AAR triplet analysis has appeared to be capable of explaining or predicting the development of non-DSAs in kidney allograft recipients (Lobashevsky et al, 2002;Adeyi et al, 2005); however, subsequent clinical studies of alloantibody profiles in post-transplant nephrectomized TCs have demonstrated that the HLAMatchmaker computer algorithm provides an incomplete HLA epitope repertoire.…”

“…During the last two decades, however, protocols using pooled human IVIG and/or plasmapheresis (PP) have been shown to eliminate some or all DSAs (Jordan et al, 2004(Jordan et al, , 2006Reinsmoen et al, 2008;Rogers et al, 2011;Thielke et al, -2005;Claas et al, 2004;Gloor et al, 2004;Stegall et al, 2009;Leong et al, 2008). Furthermore, a beneficial effect of IVIG/PP treatment for AMR has been reported by many transplant centers (Akalin et al, 2008;Furth et al, 1999;Lehrich et al, 2005;Rifle & Mousson, 2003;Toyoda et al, 2004;Vo et al, 2010).…”