The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys... Show moreThe Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLADR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.530.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation. Show less
Tambur, A.R.; Bestard, O.; Campbell, P.; Chong, A.S.; Crespo, M.; Ford, M.L.; ... ; Nickerson, P. 2023
The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and... Show moreThe Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies. Show less
Highly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for... Show moreHighly sensitized kidney patients accrue on the transplant waiting list due to their broad immunization against non-self Human Leucocyte Antigens (HLA). Although challenging, the best option for highly sensitized patients is transplantation with a crossmatch negative donor without any additional therapeutic intervention. The Eurotransplant Acceptable Mismatch (AM) program was initiated more than 30 years ago with the intention to increase the chance for highly sensitized patients to be transplanted with such a compatible donor. The AM program allows for enhanced transplantation to this difficult to transplant patient group by allocating deceased donor kidneys on the basis of a match with the recipient's own HLA antigens in combination with predefined acceptable antigens. Acceptable antigens are those HLA antigens towards which the patients has never formed antibodies, as determined by extensive laboratory testing. By using this extended HLA phenotype for allocation and giving priority whenever a compatible donor organ becomes available, organ offers are made for roughly 80% of patients in this program. Up till now, more than 1700 highly sensitized patients have been transplanted through the AM program. Recent studies have shown that the concept of acceptable mismatches being truly immunologically acceptable holds true for both rejection rates and long-term graft survival. Patients that were transplanted through the AM program had a similar rejection incidence and long-term graft survival rates identical to non-sensitized patients transplanted through regular allocation. However, a subset of patients included in the AM program does not receive an organ offer within a reasonable time frame. As these are often patients with a rare HLA phenotype in comparison to the Eurotransplant donor population, extension of the donor pool for these specific patients through further European collaboration would significantly increase their chances of being transplanted. For those patients that will not benefit from such strategy, desensitization is the ultimate solution. Show less
Kramer, C.S.M.; Franke-van Dijk, M.E.I.; Bakker, K.H.; Uyar-Mercankaya, M.; Karahan, G.E.; Roelen, D.L.; ... ; Heidt, S. 2020
In kidney transplantation, eplet mismatches between donor and recipient have been associated with de novo donor-specific antibody development. Eplets are theoretically defined configurations of... Show moreIn kidney transplantation, eplet mismatches between donor and recipient have been associated with de novo donor-specific antibody development. Eplets are theoretically defined configurations of polymorphic amino acids and require experimental verification to establish whether they can be bound by alloantibodies. Human HLA-specific monoclonal antibodies (mAbs) have been instrumental for this purpose but are largely lacking for HLA class II. In this study, we isolated single HLA-DR-specific memory B cells from peripheral blood of immunized individuals (n = 3) using HLA class II tetramers to generate recombinant human HLA-DR antigen-reactive mAbs (n = 5). Comparison of the amino acid composition of the reactive HLA alleles in relation to the antibody reactivity patterns led to identification of 3 configurations, 70Q 73A, 31F 32Y 37Y, and 14K 25Q recognized, respectively, by HLA-DRB1*01:01, HLA-DRB1*04:01, and HLA-DRB1*07:01 antigen-reactive mAbs. The first 2 correspond to eplets 70QA and 31FYY and can now be considered antibody verified. The latter indicates that eplet 25Q needs to be redefined before being considered as antibody verified. Generation and reactivity analysis of human HLA-DR mAbs allowed for identification of amino acid configurations corresponding to known eplets, whereas the other patterns may be used to redefine eplets with similar, but not identical predicted amino acid composition. Show less
Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing... Show moreWorldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, including the elderly. Only 3% of patients aged 65 years or older accepted on the waiting list actually received a kidney transplant offer within the Eurotransplant allocation region. To increase the chance for elderly to receive a timely kidney transplant, the Eurotransplant Senior Program was introduced. The ESP supports local allocation of older kidneys to older donors in order to decrease cold ischemia time, while disregarding former exchange principles based on matching for HLA antigens. As a consequence, more elderly received a kidney transplant and a relative higher incidence of acute rejection resulted in additional courses of high steroids and/or depleting antibody therapy. Since death with a functioning graft due to infections is the dominant reason of graft loss in elderly, more intense clinical immunosuppression to prevent or treat acute rejection is not a very attractive option. Therefore in elderly kidney transplant candidates, we advocate reintroduction of minimal histocompatibility criteria (i.e., HLA-DR matching) followed by age-matching with mandatory local/regional allocation to also facilitate short cold ischemia. Show less
Abacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir... Show moreAbacavir administration is associated with drug-induced hypersensitivity reactions in HIV+ individuals expressing the HLA-B*57:01 allele. However, the immunological effects of abacavir administration in an HLA-B57 mismatched transplantation setting have not been studied. We hypothesized that abacavir exposure could induce de novo HLA-B57-specific allorecognition. HIV-specific CD8 T cell clones were generated from HIV+ individuals, using single cell sorting based on HIV peptide/HLA tetramer staining. The T cell clones were assayed for alloreactivity against a panel of single HLA-expressing cell lines, in the presence or absence of abacavir. Cytokine assay, CD137 upregulation, and cytotoxicity were used as readout. Abacavir exposure can induce de novo HLA-B57 allorecognition by HIV-specific T cells. A HIV Gag RK9/HLA-A3-specific T cell did exhibit interferon-gamma production, CD137 upregulation, and cytolytic effector function against allogeneic HLA-B57, but only in the presence of abacavir. Allorecognition was specific to the virus specificity, HLA restriction, and T cell receptor TRBV use of the T cell. We provide proof-of-principle evidence that administration of a drug could induce specific allorecognition of mismatched HLA molecules in the transplant setting. We suggest that HIV-seropositive recipients of an HLA-B57 mismatched graft should not receive abacavir until further studies are completed. Show less
