Ilias I. N. Doxiadis

Long lasting debates in the past questioned the relevance of any sort of compatibility in post mortal kidney transplantation. It is for no say that fully compatible transplants have the highest chances for a long patient and graft survival. In the present report the use of HLA-DR as a representative of the Major Histocompatibility Complex class II genes in the allocation of organs is discussed. The major arguments are the easiness to offer to patients a compatible graft in a relatively short waiting time, an increase in graft survival, the less sensitization during the transplantation period, and the lower waiting time for a retransplant. Even if the number of organ donors remains the same a lowering of the mean waiting time is expected because of the longer period of graft survival.

The purpose of the study was to compare three different methods defining donor-specific antibodies (DSA): complement-dependent cytotoxicity (CDC), the flow cytometry method (FCM), and a special for that purpose commercially available Luminex-based solid phase assay (SPA). A panel of human monoclonal antibodies (HuMabs) with well-defined human leukocyte antigen (HLA) specificities was used as antibody source and single HLA antigen expressing cell lines (SAL) were used as targets. Two methods yielded identical results (CDC and FCM). However, the SPA, the method by which solubilized HLA molecules from the SAL are captured by microspheres, showed two additional reactions which could not be explained, neither by the epitope recognized by the HuMab nor by the widely accepted sensitivity of the SPA methodology. These unexplained results suggest that by capturing solubilized HLA molecules on microspheres, conformational changes might occur. Positive results obtained by similar Luminex-based microsphere methods should be therefore taken with caution and the 'recognized' HLA antigens should not automatically be considered as unacceptable for transplantation.

Here, we elaborate on one of the challenges in the current era of organ transplantation: to offer suitable organs to highly sensitized patients. Desensitization protocols and the use of an acceptable mismatch program are discussed. New protocols have been proposed for highly sensitized patients by using, in addition to intravenous immunoglobulin, an anti-CD20 monoclonal antibody (rituximab). The results look very promising for the short-term outcome. The long-term data are still pending. A new 'old' drug is proposed for elimination of the antibody-producing plasma cells, bortezomib, and may serve as a useful addition to the current protocols. The chances of highly sensitized patients to receive a crossmatch negative organ via the acceptable mismatch program can be calculated (http://etrl.eurotransplant.nl/cms/index.php) allowing, in case of a very low probability, for an offer to enroll the patient at an early stage in a desensitization protocol. The short- and long-term graft survival of highly sensitized patients transplanted via the Acceptable Mismatch protocol are excellent but, unfortunately, not all patients can be transplanted via this approach. Especially for these patients, desensitization therapies are the only solution. A comprehensive use of both alternatives, desensitization and acceptable mismatch program, seems to be the good way to go.

Background. The introduction of human leukocyte antigen (HLA)-matching in nonliving kidney transplantation has resulted into a better graft outcome, but also in an increase of waiting time, especially for patients with rare HLA phenotypes. We addressed the question of the differential influence of HLA-DR-matching versus HLA-A,B in clinical kidney transplantation. Methods. We used Kaplan-Meier product limit method to estimate survival rates, and Cox proportional hazard regression for the estimation of relative risks (Hazard-ratios) for different variables. Results. A single center study (n=456 transplants, performed between 1985 and 1999) showed that full HLA-DR compatibility leads to a lower incidence of biopsy confirmed acute rejections in the first 180 posttransplantation days. These results were substantiated using the Eurotransplant database (n=39,205 transplants performed between 1985 and 2005) where graft survival in the full HLA-DR compatible group was significantly better than in the incompatible. An additional positive effect of HLA-A,B matching was only found in the full HLA-DR compatible group. In both studies, the introduction of a single HLA-DR incompatibility eliminates the HLA-A,B matching effect. Conclusions. We propose to allocate postmortem kidneys only to patients with full HLA-DR compatibility, and use HLA-A,B compatibility as an additional selection criterion. All patients, irrespective of their ethnic origin, will profit since the polymorphism of HLA-DR is by far lower than that of HLA-A,B. Excessive kidney travel and cold ischemia time will be significantly reduced.

Background. Human leukocyte antigen (HLA)-C is expressed on nucleated cells and platelets in lower levels than HLA-A,B, and its antigens are in linkage disequilibrium with HLA-B antigens. Therefore, HLA-C antibody detection is difficult. The authors questioned whether HLA-C could serve as a target in clinical kidney transplantation using a newly developed assay. Methods. Flow cytometry was performed with sera from patients (n=34) awaiting a kidney retransplant using nine cell lines expressing a single HLA-C antigen (single-antigen lines [SAL]). Results. The SAL were validated with HLA-C–specific alloantisera and human monoclonal antibodies against HLA-A, -B, and -C. The results were in agreement with the specificities previously reported. Exceptions, because of new HLA-C specificities used here, could be explained by epitope sharing between the antigens. With respect to patient sera, 15 of the 34 patients tested (44%) showed serum reactivity toward one or more HLA-C SAL. Conclusions. In contrast to peripheral blood lymphocytes, SAL are excellent targets for detecting HLA-C–reactive alloantibodies by flow cytometry. This preliminary analysis revealed that HLA-C–reactive antibodies are frequently present in sera of retransplant patients, serving as possible targets in clinical transplantation.