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      Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients

      brief-report
      1 , , 1 , 1 , 1 , 2 , 2 , 3 , 3 , 3 , 4 , 4 , 2 , 2 , 5 , 5 , 5 , 6 , 2 , 2 , 7 , 7 , 8 , 8 , 8 , 8 , 9 , 9 , 9 , 10 , 10 , 10 , 11 , 11 , 12 , 12 , 13 , 13 , 13 , 13 , 14 , 15 , 15 , 16 , 2 , 17 , 1
      American Journal of Transplantation
      John Wiley and Sons Inc.
      alloantibody, clinical research/practice, histocompatibility, immunogenetics, kidney transplantation/nephrology, major histocompatibility complex (MHC), rejection

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          Abstract

          Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch ( AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long‐term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995‐2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6‐month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA‐B plus 1 HLADR, or 2 HLADR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low‐risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals.

          Abstract

          The authors show that kidney allocation to highly sensitized patients based on proven acceptable HLA antigens results in a significantly lower incidence of rejection episodes when compared to allocation based on the avoidance of unacceptable HLA antigens only.

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          Most cited references20

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          De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy.

          The importance of human leukocyte antigen (HLA) matching in renal transplantation is well recognized, with HLA-DR compatibility having the greatest influence. De novo DQ donor-specific antibodies (DSAbs) are the predominant HLA class II DSAb after transplantation. The aim of this study was to establish the incidence and outcomes after the development of DQ DSAbs along with the impact of class II HLA mismatch on their development. We retrospectively analyzed 505 patients who received a renal-alone transplant between 2005 and 2010. We excluded patients who received an ABO- and HLA-incompatible allograft, which we defined as those with a positive crossmatch or preformed DSAbs detected by single-antigen beads only. Of 505 patients, 92 (18.2%) developed DSAbs, with 50 (54.3%) of these 92 patients having DQ DSAbs. Patients who developed DQ DSAbs were at significant risk for antibody-mediated rejection, transplant glomerulopathy, and allograft loss (P<0.0001). Of 505 patients, 108 (21.4%) were matched at both the DR and DQ loci, 284 (56.2%) were mismatched at both loci, 38 (7.5%) were matched at DR alone, and 75 (14.9%) were matched at DQ alone. Patients mismatched at both DR and DQ were at risk for developing class II DSAbs when compared with those mismatched at either DR or DQ alone, P=0.001, and were at risk for antibody-mediated rejection, P=0.001. DQ DSAbs are associated with inferior allograft outcomes. This study shows the importance of establishing the DQ match before transplantation to define immunologic risk.
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            Clinical relevance of pretransplant donor-specific HLA antibodies detected by single-antigen flow-beads.

            Defining the clinical relevance of donor-specific HLA-antibodies detected by single-antigen flow-beads (SAFB) is important because these assays are increasingly used for pretransplant risk assessment and organ allocation. The aims of this study were to investigate to which extent HLA-DSA detected by SAFB represent a risk for antibody-mediated rejection (AMR) and diminished allograft survival, and to define HLA-DSA characteristics predictive for AMR. In this retrospective study of 334 patients with negative complement-dependent cytotoxicity crossmatches, day-of-transplant sera were analyzed by SAFB, HLA-DSA determined by virtual crossmatching, and the results correlated with the occurrence of AMR and allograft survival. Sixty-seven of 334 patients (20%) had HLA-DSA. The incidence of clinical/subclinical AMR at day 200 posttransplant was significantly higher in patients with HLA-DSA than in patients without HLA-DSA (55% vs. 6%; P<0.0001). Notably, 30/67 patients with HLA-DSA (45%) did not experience clinical/subclinical AMR. Death-censored 5-year allograft survival was equal in patient without HLA-DSA and patients with HLA-DSA but no AMR (89% vs. 87%; P=0.95), whereas it was 20% lower in patients with HLA-DSA and AMR (68%; P=0.002). The number, class, and cumulative strength of HLA-DSA determined by SAFB, and prior sensitizing events were not predictive for the occurrence of AMR. These results support the utility of SAFB for pretransplant risk assessment and organ allocation, and suggest that improvement of the positive predictive value of HLA-DSA defined by SAFB will require an enhanced definition of pathogenic factors of HLA-DSA.
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              Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation.

              This study analyzes the influence of preformed DSA, identified by HLA-specific ELISA assays, on graft survival and evaluates the incidence of antibody-mediated rejection (AMR) in patients with and without pregraft desensitization. Kidney graft survival at 8 years was significantly worse in patients with DSA (n = 43) than in those without DSA (n = 194)(p = 0.03). The incidence of AMR in patients with DSA is 9-fold higher than in patients without DSA (p < 0.001) and their graft survival is significantly worse than in DSA patients without AMR and in non-DSA patients (p = 0.005). The prevalence for AMR in patients with DSA detected on historic serum is 32.3% in nondesensitized patients and 41.7% in desensitized patients. The risk for AMR is significantly more elevated in patients with strongly positive DSA (score 6-8) compared to those with DSA score 4 (p < 0.001), and in patients with historic DSA+/CXM+ compared to those with DSA+/CXM- (p = 0.01). The presence of preformed DSA is strongly associated with graft loss in kidney transplants, related to an increased risk of AMR. Our findings demonstrate the importance of detection and characterization of DSA before transplantation. Stratification of this risk could be used to determine kidney allocation and to devise specific strategies for these patients.
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                Author and article information

                Contributors
                s.heidt@lumc.nl
                Journal
                Am J Transplant
                Am. J. Transplant
                10.1111/(ISSN)1600-6143
                AJT
                American Journal of Transplantation
                John Wiley and Sons Inc. (Hoboken )
                1600-6135
                1600-6143
                01 July 2019
                October 2019
                : 19
                : 10 ( doiID: 10.1111/ajt.v19.10 )
                : 2926-2933
                Affiliations
                [ 1 ] Eurotransplant Reference Laboratory Leiden University Medical Center Leiden the Netherlands
                [ 2 ] Laboratory of Translational Immunology University Medical Center Utrecht Utrecht University Utrecht the Netherlands
                [ 3 ] Radboud University Medical Center Radboud Institute for Molecular Life Sciences Laboratory Medicine Laboratory of Medical Immunology Nijmegen the Netherlands
                [ 4 ] Radboud University Medical Center Department of Nephrology Radboud Institute for Health Sciences Nijmegen the Netherlands
                [ 5 ] Department of Nephrology and Hypertension University Medical Center Utrecht Utrecht University Utrecht the Netherlands
                [ 6 ] Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht University Utrecht the Netherlands
                [ 7 ] Department of Nephrology University of Groningen University Medical Center Groningen Groningen the Netherlands
                [ 8 ] Department of Laboratory Medicine University of Groningen University Medical Center Groningen Groningen the Netherlands
                [ 9 ] Department of Transplantation Immunology Tissue Typing Laboratory Maastricht University Medical Centre Maastricht the Netherlands
                [ 10 ] Department of Internal Medicine Division of Nephrology Maastricht University Medical Centre Maastricht the Netherlands
                [ 11 ] Department of Nephrology Amsterdam University Medical Center Vrije Universiteit Amsterdam Amsterdam the Netherlands
                [ 12 ] Department of Immunogenetics Sanquin Diagnostic Services Amsterdam the Netherlands
                [ 13 ] Department of Internal Medicine Amsterdam University Medical Center University of Amsterdam Renal Transplant Unit Amsterdam the Netherlands
                [ 14 ] Dutch Organ Transplant Registry (NOTR) Dutch Transplant Foundation (NTS) Leiden the Netherlands
                [ 15 ] Department of Nephrology Leiden University Medical Center Leiden the Netherlands
                [ 16 ] Department of Nephrology Erasmus Medical Center Rotterdam the Netherlands
                [ 17 ] Department of Immunohematology and Blood Transfusion Leiden University Medical Center Leiden the Netherlands
                Author notes
                [*] [* ] Correspondence

                Sebastiaan Heidt

                Email: s.heidt@ 123456lumc.nl

                Author information
                https://orcid.org/0000-0002-6700-188X
                https://orcid.org/0000-0002-6927-2683
                https://orcid.org/0000-0001-9435-6208
                Article
                AJT15486
                10.1111/ajt.15486
                6790659
                31155833
                a3ae1078-d212-418c-a36b-063ab0e91e54
                © 2019 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 02 February 2019
                : 04 May 2019
                : 08 May 2019
                Page count
                Figures: 2, Tables: 2, Pages: 8, Words: 5975
                Categories
                Brief Communication
                Brief Communications
                Custom metadata
                2.0
                October 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.0 mode:remove_FC converted:14.10.2019

                Transplantation
                alloantibody,clinical research/practice,histocompatibility,immunogenetics,kidney transplantation/nephrology,major histocompatibility complex (mhc),rejection

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