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Abbas K, Mubarak M, Musharraf W, Hafeez AR, Aziz T, Zafar MN. Impact of low-level pretransplant donor-specific antibodies detected by the Luminex platform on acute rejection and long-term graft survival. World J Transplant 2025; 15:104308. [DOI: 10.5500/wjt.v15.i3.104308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/02/2025] [Accepted: 03/10/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND The Luminex platform, where beads are coated with single human leukocyte antigens (HLA), detects HLA antibodies with higher sensitivity and specificity compared to complement-dependent cytotoxicity (CDC) assay and flow cross-match (FCXM). The clinical significance of donor-specific antibodies (DSAs) detected by this method is still under investigation.
AIM To report the impact of low-level pretransplant DSAs detected by the Luminex platform on the rates of acute rejection (AR), allograft function, and long-term graft survival.
METHODS This retrospective study was conducted at the Immunology Department of Sindh Institute of Urology and Transplantation, Karachi, Pakistan between January 2013 and December 2022. During this period 2714 patients were transplanted. Out of these patients 78 (2.9%) patients had low-level DSAs detected by the Luminex flow beads method and were negative by CDC and FCXM with their donors. All recipients received ABO-compatible live-related kidney transplants. All patients had a minimum follow-up of 1 year. Graft rejection rates, graft function, and patient and graft survival were analyzed. The estimated glomerular filtration rate was calculated by the full CKD-EPI formula.
RESULTS The mean age of all recipients was 29.57 ± 10.11 years and 34.53 ± 9.09 years for the donors. In 48 (61.5%) patients, the cause of end-stage kidney disease was unknown. DSA against HLA class I was detected in 36 (46.1%) patients, class II in 35 (44.8%) patients, and both class I and II in 7 (8.9%) patients. AR episodes were encountered in 8 (10.3%) cases. Seven (87.5%) had T cell mediated rejection (type IA) and one acute antibody-mediated rejection. Antibody status was re-evaluated at the time of biopsy-proven ARs. Five (62.5%) patients lost their DSAs, while three (37.5%) had persistent DSAs. The mean estimated glomerular filtration rate at 1 year was 80.56 ± 27.48 mL/min/1.73 m2 and at the last follow-up 73.41 ± 28.80 mL/min/1.73 m2. The 1-year and 10-year patient and graft survival rates were 99% and 79% and 95% and 75%, respectively. During the follow-up period, 10 (12.8%) patients died, 8 patients had a functioning graft, and 2 patients had failed grafts. Eight patients died due to cardiopulmonary arrest, and two died due to sepsis with failed grafts.
CONCLUSION Patients with pretransplant low-level DSAs on Luminex without CDC and FCXM reactivity had good allograft outcomes at 1 year and 10 years as long as they are induced with biological agents and given potent maintenance immunosuppressants.
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Affiliation(s)
- Khawar Abbas
- Department of Transplant Immunology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sind, Pakistan
| | - Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Wajiha Musharraf
- Department of Transplant Immunology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sind, Pakistan
| | - Abdul Rauf Hafeez
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Tahir Aziz
- Department of Transplantation, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Mirza Naqi Zafar
- Department of Pathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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Carpenter MC, Shrestha S, Bharadwaj P, Concetta C, Sharma S, Weiner JA, de Haan N, Pongracz T, Le Moine A, Holovska V, Marchant A, Ackerman ME. Functional and phenotypic profiles of HLA-specific antibodies in relation to antibody-mediated kidney transplant rejection. Hum Immunol 2025; 86:111247. [PMID: 39889319 PMCID: PMC11922655 DOI: 10.1016/j.humimm.2025.111247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/13/2025] [Accepted: 01/20/2025] [Indexed: 02/02/2025]
Abstract
Donor Specific Antibodies (DSAs) are associated with a higher risk of Antibody Mediated Rejection (AMR). However, not all DSAs are pathogenic, and patients that raise DSAs have a wide spectrum of outcomes ranging from the complete absence of graft injury to severe AMR. Hence, characterization of both the qualitative features and titer of DSAs has the potential to predict AMR risk and treatment outcome for sensitized patients. Here, using HLA-A2+ cell-based assays, we investigate the qualitative features of immunoglobulin G (IgG) alloantibodies including Fc receptor binding properties and Fc-mediated effector function over time. Compared to seronegative controls, reactive antibodies in seropositive participants were predominantly IgG1, and exhibited elevated levels of binding to the receptors involved in Antibody Dependent Cellular Phagocytosis (ADCP) and Antibody Dependent Cellular Cytotoxicity (ADCC) activity. Further analysis of seropositive individuals revealed that these activities were predictive ofAMR status. Collectively, these results suggest a role for phagocytic and cytotoxic antibody effector functions of DSA in contributing to graft injury.
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Affiliation(s)
| | - Sweta Shrestha
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College Hanover NH USA
| | - Pranay Bharadwaj
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College Hanover NH USA
| | - Catalano Concetta
- Institute for Medical Immunology, Université libre de Bruxelles Charleroi Belgium; Department of Nephrology, Dialysis and Renal Transplantation, Hôpital Erasme, Université libre de Bruxelles Bruxelles Belgium
| | - Shilpee Sharma
- Institute for Medical Immunology, Université libre de Bruxelles Charleroi Belgium
| | - Joshua A Weiner
- Thayer School of Engineering, Dartmouth College Hanover NH USA
| | - Noortje de Haan
- Center for Proteomics and Metabolomics Leiden University Medical Center Leiden the Netherlands
| | - Tamas Pongracz
- Center for Proteomics and Metabolomics Leiden University Medical Center Leiden the Netherlands
| | - Alain Le Moine
- Department of Nephrology, Dialysis and Renal Transplantation, Hôpital Erasme, Université libre de Bruxelles Bruxelles Belgium
| | - Vanda Holovska
- HLA Laboratory, Laboratoire Hospitalier Universitaire de Bruxelles (LHUB), Hôpital Erasme ULB Brussels Belgium
| | - Arnaud Marchant
- Institute for Medical Immunology, Université libre de Bruxelles Charleroi Belgium
| | - Margaret E Ackerman
- Thayer School of Engineering, Dartmouth College Hanover NH USA; Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Dartmouth College Hanover NH USA.
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San Segundo D, Comins-Boo A, López-Hoyos M. Anti-Human Leukocyte Antigen Antibody Detection from Terasaki's Humoral Theory to Delisting Strategies in 2024. Int J Mol Sci 2025; 26:630. [PMID: 39859344 PMCID: PMC11766285 DOI: 10.3390/ijms26020630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/03/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The human leukocyte antigen (HLA) system plays a critical role in transplant immunology, influencing outcomes through various immune-mediated rejection mechanisms. Hyperacute rejection is driven by preformed donor-specific antibodies (DSAs) targeting HLAs, leading to complement activation and graft loss within hours to days. Acute rejection typically occurs within six months post-transplantation, involving cellular and humoral responses, including the formation of de novo DSAs. Chronic rejection, a key factor in long-term graft failure, often involves class II DSAs and complex interactions between the innate and adaptive immune systems. Advancements in HLA antibody detection, particularly single antigen bead (SAB) assays, have improved the sensitivity and characterization of DSAs. However, these assays face challenges like false positives from denatured antigens and false negatives due to low antibody titers or complement competition. Furthermore, molecular mismatch (MM) analysis has emerged as a potential tool for refining donor-recipient compatibility but faces some issues such as a lack of standardization. Highly sensitized patients with calculated panel-reactive antibodies (cPRA) of 100% face barriers to transplantation. Strategies like serum dilution, novel therapies (e.g., Imlifidase), and delisting approaches could refine immunological risk assessment and delisting strategies are essential to expand transplant opportunities for these patients.
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Affiliation(s)
- David San Segundo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Alejandra Comins-Boo
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
| | - Marcos López-Hoyos
- Immunology Department, University Hospital Marqués de Valdecilla, 39008 Santander, Spain; (D.S.S.); (A.C.-B.)
- Institute for Research Marqués de Valdecilla (IDIVAL), 39011 Santander, Spain
- Departamento de Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain
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Usureau C, Lhotte R, Devriese M, Siemowski J, Gabet L, Letort V, Taupin JL. Bead-by-bead normalization of single antigen assays: A necessary step for accurate detection of weak anti-HLA antibodies. Eur J Immunol 2024; 54:e2451181. [PMID: 39233540 DOI: 10.1002/eji.202451181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 07/19/2024] [Accepted: 07/30/2024] [Indexed: 09/06/2024]
Abstract
Ascertaining the presence of weakly positive anti-HLA donor-specific antibodies (DSA) in organ transplantation with multiplex single antigen beads assays may be challenging despite their high sensitivity due to technical variability issues. Through extensive datasets of Next-Generation Sequencing HLA typings and single antigen analyses, we reassessed the mean fluorescence intensity (MFI) positivity threshold of the assay to enhance accuracy. By showing that some beads were more prone to false positivity than others, we propose a nuanced approach that accounts for nonspecific intrinsic reactivities at the HLA antigen level, that is, on a bead-by-bead basis, as it enhances assay precision and reliability. This is substantiated by a comprehensive statistical analysis of MFI values and the implementation of the determination of a "Quantile Adjusted Threshold 500" (QAT500) value for each bead. Applied to DSA detection during patients' follow-up, this approach discriminated better and earlier low-strength DSA that would later raise their MFI above the clinically relevant threshold of 3000. Moving from a subjective interpretation to a more objective and precise methodology allows for standardizing HLA antibody and DSA detection. The study emphasizes the need for further research with real clinical data to validate and refine this approach.
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Affiliation(s)
- Cédric Usureau
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France
- INSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, France
| | - Romain Lhotte
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France
- INSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, France
- MICS-Research Laboratory in Mathematics and Computer Science, Centrale Supélec, Paris-Saclay University, Gif-Sur-Yvette, France
| | - Magali Devriese
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France
- INSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, France
| | - Jérémy Siemowski
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France
| | - Lionel Gabet
- MICS-Research Laboratory in Mathematics and Computer Science, Centrale Supélec, Paris-Saclay University, Gif-Sur-Yvette, France
| | - Véronique Letort
- MICS-Research Laboratory in Mathematics and Computer Science, Centrale Supélec, Paris-Saclay University, Gif-Sur-Yvette, France
| | - Jean-Luc Taupin
- Laboratoire d'Immunologie et Histocompatibilité, Hôpital Saint Louis, Paris, France
- INSERM UMR976, Institut de Recherche Saint-Louis, Université de Paris-Cité, Paris, France
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Nadat F, Clark B. Forming a new perspective: Post-structural approaches to determination of donor compatibility and post-transplant assessment of allograft health. Int J Immunogenet 2024; 51:195-205. [PMID: 38711186 DOI: 10.1111/iji.12675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 03/25/2024] [Indexed: 05/08/2024]
Abstract
The purpose of this review is to encourage a new perspective on the question of donor-recipient compatibility and post-transplant assessment of graft health based on functional measures. The premise is that we should be better sighted on what (and how) the immune system responds toward rather than what is merely there. Continuance of the pursuit of further and better definition of antigens and antibodies is not however discouraged but seen as necessary to improved understanding of the structural correlates of functional immunity. There currently exists, in the opinion of the authors, an opportunity for histocompatibility and immunogenetics laboratories to develop and widen their scope of involvement into these new areas of laboratory activity in support and to the benefit of the transplant programmes they serve.
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Affiliation(s)
- Fatima Nadat
- Functional Assessment of Transplant Immunology Group, St James's University Hospital, Leeds, UK
| | - Brendan Clark
- Functional Assessment of Transplant Immunology Group, St James's University Hospital, Leeds, UK
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García-Jiménez S, Paz-Artal E, Trujillo H, Polanco N, Castro MJ, Del Rey MJ, Alfocea Á, Morales E, González E, Andrés A, Mancebo E. A personalised delisting strategy enables successful kidney transplantation in highly sensitised patients with preformed donor-specific anti HLA antibodies. HLA 2024; 103:e15572. [PMID: 38923242 DOI: 10.1111/tan.15572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 05/13/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024]
Abstract
This study investigates kidney transplant outcomes in highly sensitised patients after implementing a delisting strategy aimed at enabling transplantation despite preformed donor-specific antibodies (preDSA), with the goal of reducing acute antibody-mediated rejection (aAMR) risk. Fifty-three sensitised recipients underwent kidney transplant after delisting prohibited HLA antigens, focusing initially in low MFI antibodies (<5000), except for anti-HLA-DQ. If insufficient, higher MFI antibodies were permitted, especially for those without an immunogenic eplet pattern assigned. Delisting of Complement-fixing antibodies (C1q+) was consistently avoided. Comparison cohorts included 53 sensitised recipients without DSA (SwoDSA) and 53 non-sensitised (NS). The average waiting time prior to delisting was 4.4 ± 1.8 years, with a reduction in cPRA from 99.7 ± 0.5 to 98.1 ± 0.7, followed by transplantation within 7.2 ± 8.0 months (analysed in 34 patients). Rejection rates were similar among preDSA, SwoDSA, and NS groups (16%, 8%, and 11%, respectively; p = 0.46). However, aAMR was higher in the preDSA group (12%, 4%, and 2%, respectively; p = 0.073), only presented in recipients with DSA of MFI >5000. The highest MFI DSA were against HLA-DP (Median: 10796 MFI), with 50% of preDSA aAMR cases due to anti-DP antibodies (n = 3). Graft survival rates at 1 and 5 years in preDSA group were 94%, and 67%, comparable to SwoDSA (94%, and 70%; p = 0.69), being significantly higher in the NS group (p = 0.002). The five-year recipient survival rate was 89%, comparable to SwoDSA and NS groups (p = 0.79). A delisting strategy enables safe kidney transplant in highly sensitised patients with preDSA, with a slight increase in aAMR and comparable graft and patient survivals to non-DSA cohorts.
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Affiliation(s)
- Sandra García-Jiménez
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Estela Paz-Artal
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
- School of Medicine, Complutense University of Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Infecciosas, Instituto de Salud Carlos III, Madrid, Spain
| | - Hernando Trujillo
- Nephrology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Natalia Polanco
- Nephrology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - María J Castro
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Manuel J Del Rey
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Ángel Alfocea
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Enrique Morales
- School of Medicine, Complutense University of Madrid, Madrid, Spain
- Nephrology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Esther González
- Nephrology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Amado Andrés
- School of Medicine, Complutense University of Madrid, Madrid, Spain
- Nephrology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
| | - Esther Mancebo
- Immunology Department, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre (imas12), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
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7
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Shi QS, Jiang X, Li M, Fang J, Fu Z, Zhu S, Wu C, Meng Q, Jie T, Askar M. Microvascular activation and exocytosis after exposure to the serum from mismatched recipients by using donor microvascular cultures. Transpl Immunol 2024; 82:101963. [PMID: 38013122 DOI: 10.1016/j.trim.2023.101963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 11/29/2023]
Abstract
BACKGROUND Microvascular injury resulting from activation and exocytosis are early signs of tissue damage caused by allografting. However, humoral anti-graft reactions are not easily detectable in transplant biopsies. The aim of this study was to establish a bioassay to recapitulate this process in a prospective approach. METHODS The study was executed by using our previously established protocol to isolate and freeze the donors' microvascular endothelial cells (MVEC) at the transplantation (34 living-related donors and 26 cadaver donors); and to collect sera from the recipients before the transplantation, one-, three- and six-months after transplantation. The activation and exocytosis of the MVEC were determined by incubating the donors' cultures with the recipients' sera. We determined if there was any endothelial activation by quantifying the releases of monocyte chemotactic protein-1 (MCP-1) and interleukin 8 (IL-8) in supernatants and the expressions of membrane intercellular adhesion molecule-1 (CD54) and intercellular adhesion molecule-1 (CD106) by flow cytometry. Endothelial exocytosis was determined by quantifying soluble E-selectin (CD62E) and cytoplasmic von Willebrand Factor (vWF) in supernatants. Endothelial activation or exocytosis was considered positive when the fold change (≧1.5) of post-transplantation to pre-transplantation was reached. We also monitored serum PRA and cytokines using Luminex multiple-plex and cytometric bead-based assay respectively. RESULTS We found 41.2% recipients (14 out of 34, ranging from 1.5 to 5.2 folds, p < 0.05) exhibited positive MVEC activation in the first month after transplantation as determined by IL-8 levels; 26.5% recipients (9 out of 34, ranging from 1.5 to 11.8 folds, p < 0.05) by MCP-1 levels. In the group of three months post-transplantation, 70.6% patients were positive (12 out of 17, ranging from 1.8 to 87.1 folds, p < 0.05) by IL-8 increased levels; 24% recipients (4 out of 17, ranging from 1.8 to 50.5 folds, p < 0.05) measured by MCP-1 levels. However, these changes disappeared six months after transplantation. Flow cytometric data showed that a time-dependent of CD54+ and CD106+ expressions existed over the course of six months. Most CD54+ and CD106+ cells were CD31- (platelet-endothelial cell adhesion molecule-1), though CD31+/CD106+ (37.5%, 3 out of 8) and CD31+/CD106+ (25%. 2 out of 8) were seen. When comparing donor MVEC activation to their recipient's proinflammatory cytokine levels or PRA status, we could not draw a conclusion regarding the connections between them. The sera collected from recipients at either one- or three-months after allografting did not significantly induce the release of either soluble CD62E or vWF (p > 0.05), indicating exocytosis was not significantly involved in the acute phase of allografting. CONCLUSIONS This bioassay enables us to detect the activation and exocytosis of donor MVEC elicited by respective sera from mismatched kidney recipients.
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Affiliation(s)
- Qiang Sebastian Shi
- Minnie & Max T. Voelcker Laboratory, Tianjin International Joint Academy of Bio-medicine, S1515 Room, 220 Dongting Road, TEDA, Tianjin, China; Minnie & Max T. Voelcker Laboratory (Suzhou), 1304 Room No. 1 Building, 399 Xiarong Street, Wujiang District, Suzhou, China.
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Medical College of Henan University of Chinese Medicine, 33 Huanghe Road, Zhengzhou, Henan Province, China.
| | - Ming Li
- Department of Organ Transplantation, The Fifth Medical College of Henan University of Chinese Medicine, 33 Huanghe Road, Zhengzhou, Henan Province, China
| | - Jun Fang
- Department of Organ Transplantation, The Fifth Medical College of Henan University of Chinese Medicine, 33 Huanghe Road, Zhengzhou, Henan Province, China
| | - Zhiqiang Fu
- The Eco-City Hospital of Tianjin Fifth Central Hospital, 3333 He-Chang Road, Eco-City, Tianjin 300367, China
| | - Shengyi Zhu
- Minnie & Max T. Voelcker Laboratory (Suzhou), 1304 Room No. 1 Building, 399 Xiarong Street, Wujiang District, Suzhou, China.
| | - Chengyu Wu
- Transplant Immunology Laboratory, Central Texas Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508, USA.
| | - Qianghe Meng
- Department of Surgery, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
| | - Tun Jie
- Transplant Immunology Laboratory, Central Texas Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508, USA.
| | - Medhat Askar
- Transplant Immunology, Baylor University Medical Center, 3500 Gaston Ave, 4th Floor of the Y Wing, RM# L-0470, Dallas, TX 75246, USA.
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İnal A, Taş D, Yarbuğ Karakayalı F, Uysal A, Ogan Uyanık E, Kaba H. Superiority of Single-Antigen Bead Study in Donor-Specific Antibodies: Determination in Highly Sensitized Patients. EXP CLIN TRANSPLANT 2024; 22:332-335. [PMID: 38385420 DOI: 10.6002/ect.mesot2023.p116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
OBJECTIVES The presence of donor-specific antibodies against HLA before kidney transplant has been variably associated with decreased long-term graft survival. Data on the association between pretransplant donor-specific antibodies and rejection and cause of graft failure in recipients of donor kidneys are scarce. MATERIALS AND METHODS For this study of HLA antibody levels, we analyzed serum samples from 76 patients (48 women and 28 men) who were prepared for kidney transplant at the Baskent University İstanbul Hospital between 2017 and 2022. Levels were determined by using Lifecodes panel reactive antibody class I and II identification kits and Lifecodes LSA class I and II identification kits by the Luminex assay method. RESULTS Multiple antigen tests showed more than 70% sensitization detected against both class I and class II antigens in our patient group. When some samples were reevaluated with the single-antigen bead method, desensitization values were shown to be considerably reduced compared with values from multiple antigen methods. CONCLUSIONS The single-antigen-coated bead method can be useful in determining the risk of donor-specific antibodies in highly sensitized patients.
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Affiliation(s)
- Ali İnal
- From the Immunology Department, Baskent University Medical Faculty, Istanbul, Turkey
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9
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Chowdhry M, Yadav A, Sharma V, Agrawal S. Role of therapeutic plasma exchange as a desensitization therapy in human leukocyte antigen incompatible renal transplant patients: A single-center experience. Hematol Transfus Cell Ther 2024; 46:42-48. [PMID: 36621348 PMCID: PMC10935460 DOI: 10.1016/j.htct.2022.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 09/09/2022] [Accepted: 11/16/2022] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Despite an increase in the rate of successful live donor renal transplantation done annually, the number of potential recipients with acceptable donors is relegated to the ever-expanding cadaver-donor waiting list due to sensitization to human leukocyte antigen (HLA) antibodies. If not sufficiently suppressed, these preformed HLA antibodies can trigger antimicrobial resistance (AMR) and early graft loss. To ameliorate this situation, various desensitization treatments are administered to provide a survival benefit to highly sensitized patients. METHOD One hundred and six patients in the time frame of January 2017 to March 2019 were included in the study group. The desensitization protocol included therapeutic plasma exchange and administration of low-dose intravenous immunoglobulin (100 mg/kg per therapeutic plasma exchange (TPE) session) to highly sensitized patients (treatment group) who subsequently underwent renal transplantation after negative pre-transplant Centers for Disease Control and Prevention Luminex crossmatch (CDC/LumXM). We compared graft survival rates between the group undergoing desensitization (treatment group) and matched control group of patients that underwent HLA-compatible transplantation. RESULTS In the treatment group, Kaplan-Meier analysis estimates an average rate of patient graft survival of 95.2% at 3 years post-transplant, as compared with the rate of 86.9% in the same time frame for the control-matched group (p < 0.05 for both comparisons). CONCLUSION Desensitization treatment with TPE before live donor renal transplantation in the case of patients with HLA sensitization provides better survival benefits along with monitoring for donor-specific antibodies (DSAs) and other infections, rather than waiting for a compatible organ donor. The data lays out evidence that desensitization treatments can assist overcome HLA incompatibility barriers in live donor renal transplantation.
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Affiliation(s)
- Mohit Chowdhry
- Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, New Delhi 110076, India.
| | - Ayushi Yadav
- Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, New Delhi 110076, India
| | - Vandana Sharma
- Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, New Delhi 110076, India
| | - Soma Agrawal
- Department of Transfusion Medicine, Indraprastha Apollo Hospitals, Sarita Vihar, Mathura Road, New Delhi 110076, India
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10
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Cornaby C, Weimer ET. Utilizing principal component analysis in the identification of clinically relevant changes in patient HLA single antigen bead solid phase testing patterns. PLoS One 2023; 18:e0288743. [PMID: 37883384 PMCID: PMC10602234 DOI: 10.1371/journal.pone.0288743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 07/04/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND HLA antibody testing is essential for successful solid-organ allocation, patient monitoring post-transplant, and risk assessment for both solid-organ and hematopoietic transplant patients. Luminex solid-phase testing is the most common method for identifying HLA antibody specificities, making it one of the most complex immunoassays as each panel contains over 90 specificities for both HLA class I and HLA class II with most of the analysis being performed manually in the vendor-provided software. Principal component analysis (PCA), used in machine learning, is a feature extraction method often utilized to assess data with many variables. METHODS & FINDINGS In our study, solid organ transplant patients who exhibited HLA donor-specific antibodies (DSAs) were used to characterize the utility of PCA-derived analysis when compared to a control group of post-transplant and pre-transplant patients. ROC analysis was utilized to determine a potential threshold for the PCA-derived analysis that would indicate a significant change in a patient's single antigen bead pattern. To evaluate if the algorithm could identify differences in patterns on HLA class I and HLA class II single antigen bead results using the optimized threshold, HLA antibody test results were analyzed using PCA-derived analysis and compared to the clinical results for each patient sample. The PCA-derived algorithm had a sensitivity of 100% (95% CI, 73.54%-100%), a specificity of 75% (95% CI, 56.30%-92.54%), with a PPV of 65% (95% CI, 52.50%-83.90%) and an NPV of 100%, in identifying new reactivity that differed from the patients historic HLA antibody pattern. Additionally, PCA-derived analysis was utilized to assess the potential over-reactivity of single antigen beads for both HLA class I and HLA class II antibody panels. This assessment of antibody results identified several beads in both the HLA class I and HLA class II antibody panel which exhibit over reactivity from 2018 to the present time. CONCLUSIONS PCA-derived analysis would be ideal to help automatically identify patient samples that have an HLA antibody pattern of reactivity consistent with their history and those which exhibit changes in their antibody patterns which could include donor-specific antibodies, de novo HLA antibodies, and assay interference. A similar method could also be applied to evaluate the over-reactivity of beads in the HLA solid phase assays which would be beneficial for lot comparisons and instructive for transplant centers to better understand which beads are more prone to exhibiting over-reactivity and impact patient care.
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Affiliation(s)
- Caleb Cornaby
- Histocompatibility & Diagnostic Immunology Laboratory, Children's Hospital of Los Angeles, Los Angeles, California, United States of America
- Department of Pathology and Laboratory Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America
| | - Eric T Weimer
- Molecular Immunology Laboratory, McLendon Clinical Laboratories, UNC Health, Chapel Hill, North Carolina, United States of America
- Department of Pathology & Laboratory Medicine, the University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, United States of America
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11
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Hug MN, Keller S, Marty T, Gygax D, Meinel D, Spies P, Handschin J, Kleiser M, Vazquez N, Linnik J, Buchli R, Claas F, Heidt S, Kramer CSM, Bezstarosti S, Lee JH, Schaub S, Hönger G. HLA antibody affinity determination: From HLA-specific monoclonal antibodies to donor HLA specific antibodies (DSA) in patient serum. HLA 2023. [PMID: 37191252 DOI: 10.1111/tan.15047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/08/2023] [Accepted: 03/20/2023] [Indexed: 05/17/2023]
Abstract
Organs transplanted across donor-specific HLA antibodies (DSA) are associated with a variety of clinical outcomes, including a high risk of acute kidney graft rejection. Unfortunately, the currently available assays to determine DSA characteristics are insufficient to clearly discriminate between potentially harmless and harmful DSA. To further explore the hazard potential of DSA, their concentration and binding strength to their natural target, using soluble HLA, may be informative. There are currently a number of biophysical technologies available that allow the assessment of antibody binding strength. However, these methods require prior knowledge of antibody concentrations. Our objective within this study was to develop a novel approach that combines the determination of DSA-affinity as well as DSA-concentration for patient sample evaluation within one assay. We initially tested the reproducibility of previously reported affinities of human HLA-specific monoclonal antibodies and assessed the technology-specific precision of the obtained results on multiple platforms, including surface plasmon resonance (SPR), bio-layer interferometry (BLI), Luminex (single antigen beads; SAB), and flow-induced dispersion analysis (FIDA). While the first three (solid-phase) technologies revealed comparable high binding-strengths, suggesting measurement of avidity, the latter (in-solution) approach revealed slightly lower binding-strengths, presumably indicating measurement of affinity. We believe that our newly developed in-solution FIDA-assay is particularly suitable to provide useful clinical information by not just measuring DSA-affinities in patient serum samples but simultaneously delivering a particular DSA-concentration. Here, we investigated DSA from 20 pre-transplant patients, all of whom showed negative CDC-crossmatch results with donor cells and SAB signals ranging between 571 and 14899 mean fluorescence intensity (MFI). DSA-concentrations were found in the range between 11.2 and 1223 nM (median 81.1 nM), and their measured affinities fall between 0.055 and 24.7 nM (median 5.34 nM; 449-fold difference). In 13 of 20 sera (65%), DSA accounted for more than 0.1% of total serum antibodies, and 4/20 sera (20%) revealed a proportion of DSA even higher than 1%. To conclude, this study strengthens the presumption that pre-transplant patient DSA consists of various concentrations and different net affinities. Validation of these results in a larger patient cohort with clinical outcomes will be essential in a further step to assess the clinical relevance of DSA-concentration and DSA-affinity.
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Affiliation(s)
- Melanie N Hug
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Sabrina Keller
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Talea Marty
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Daniel Gygax
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Dominik Meinel
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Peter Spies
- University of Applied Sciences and Arts Northwestern Switzerland, School of Life Sciences Muttenz, Muttenz, Switzerland
| | - Joëlle Handschin
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marc Kleiser
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Noemi Vazquez
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Janina Linnik
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland
- Swiss Institute for Bioinformatics, Basel, Switzerland
| | - Rico Buchli
- Department of Research and Development, PureProtein LLC, Oklahoma City, Oklahoma, USA
| | - Frans Claas
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Cynthia S M Kramer
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Suzanne Bezstarosti
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Jar-How Lee
- Research Department, Terasaki Innovation Center (TIC), Glendale, California, USA
| | - Stefan Schaub
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Gideon Hönger
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
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12
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Abbas K, Aziz T, Musharaf W, Mubarak M, Zafar MN. Impact of pre-transplant donor specific antibodies detected by Luminex with negative microlymphocytotoxicity assay and flow crossmatch in live-related renal transplant recipients. Clin Transplant 2023; 37:e14935. [PMID: 36799009 DOI: 10.1111/ctr.14935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/06/2022] [Accepted: 02/08/2023] [Indexed: 02/18/2023]
Abstract
INTRODUCTION/AIM The Luminex assay, where beads are coated with a single HLA antigen, has been shown to detect HLA antibodies with more sensitivity and specificity as compared to microlymphocytotoxicity (CDC) assay and flow cross match (FCXM). We report the impact of low Mean Flourescence intensity (MFI) pre-transplant DSA by Luminex with negative CDC and FCXM on acute rejection, graft function, and survival. METHODS In this retrospective study between January 2015 to December 2021, 45 recipients had pre-transplant anti-HLA donor-specific antibodies (DSAs) detected by Luminex. Two control groups of 45 patients each matched for age and gender, first with non-DSA HLA antibodies and second with no antibodies by Luminex were selected to compare outcomes with DSA group. RESULTS In the DSA group of 45, 22 (48.8%) had class I (MFI mean 4043 ± 1909, range: 1096-7111), 20 (44.4%) class II (MFI mean 3601 ± 2310, range: 1031-9259), and 3 (6.6%) both class I (MFI mean 4746 ± 1922) and class II (MFI mean 3940 ± 2312) antibodies. Acute rejection episodes were reported in 15.6%, DSA group, 17.8% in non-DSA, and 24.4% in no antibody group (p = .538). Death censored graft survival at 1 and 5 years was 98% and 93% in DSA group, 100% and 95% in non-DSA and 93% and 85% in the no antibody group (p = .254). CONCLUSIONS Patients with low MFI DSA pre-transplant, with a negative CDC and FCXM under ATG induction, have similar graft outcomes at 1 and 5 years when compared to non-DSA and no antibody groups.
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Affiliation(s)
| | - Tahir Aziz
- Transplantation Department, SIUT, Karachi, Pakistan
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13
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Pedini P, Baudey JB, Basire A, Chiaroni J, Hubert L, Picard C. Evaluation of a new complement-dependent lymphocytotoxicity cross match method using an automated cell counter, the NucleoCounter® NC-3000™. HLA 2023; 101:647-659. [PMID: 37015889 DOI: 10.1111/tan.15044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 04/06/2023]
Abstract
Complement-dependent lymphocytotoxicity cross match (CDC-XM) is the ultimate test of donor/recipient compatibility prior to organ transplantation. This test is based on cell viability, evaluated under fluorescence microscopy by an operator after proper staining. The determination of the positivity threshold may vary depending on the operator. We developed a new method in which the final step of determining cell viability is automated using the NC-3000™ (Chemometec®), an image cytometer able to precisely determine the percentage of dead/live cells in a suspension. After T and B donor cells isolation by negative selection, complement-dependent lysis was performed in macrovolumes in a PCR plate. Then, cell viability was measured by the NC-3000™. The sensitivity and routine CDC-XM results of this new method were compared to those of CDC-XM reference method using Terasaki plates. The sensitivity of CDC-XM expressed in the ASHI scoring system of this method was similar to the reference method results for a dilution range of the positive controls. Similarly, the results of the new method were comparable in a clinical situation to those obtained with the reference method after a study of 10 cross-matches, of which 5 cross-matches with DSA were positive and five cross-matches without DSA were negative. Moreover, ASHI scores were similar to those obtained using the reference method, and the mortality percentage was reproducible (CV < 15%). The assessment of cell viability by the NC-3000™ is easy to perform and highly reproducible but requires CDC-XM to be performed by the macrovolume method. The determination of a precise percentage of viability/mortality by the automation excludes operator variability and allows a better understanding of results close to the decision threshold.
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Affiliation(s)
- Pascal Pedini
- EFS PACA- Corse, Marseille, France
- UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
| | | | | | - Jacques Chiaroni
- EFS PACA- Corse, Marseille, France
- UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
| | - Lucas Hubert
- EFS PACA- Corse, Marseille, France
- UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
| | - Christophe Picard
- EFS PACA- Corse, Marseille, France
- UMR 7268 ADÉS Aix-Marseille Université/EFS/CNRS, Marseille, France
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14
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Di Cocco P, Gaitonde S, Spaggiari M, Fratti A, Alvarez JA, Petrochenkov E, Valdenepas BT, Gupta P, Benedetti E, Tzvetanov I. Desensitizing With Temporary Donor Splenic Transplant: Hope for the Sensitized Patients on Pancreas and Kidney -Pancreas Transplant Waitlist. Transplant Proc 2023; 55:295-302. [PMID: 36801174 DOI: 10.1016/j.transproceed.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/20/2022] [Accepted: 01/24/2023] [Indexed: 02/21/2023]
Abstract
BACKGROUND Sensitized patients on a waitlist with donor specific antibodies (DSA) or positive flow cytometry cross match (FXM) to deceased donor organ have few pretransplant desensitization options due to increasing graft cold ischemia time. Herein, sensitized simultaneous kidney/pancreas recipients received temporary splenic transplant from the same donor under the hypothesis that spleen would function as a DSA graveyard and provide a safe immunologic window for transplant. METHODS We analyzed presplenic and postsplenic transplant FXM and DSA results of 8 sensitized patients who underwent simultaneous kidney and pancreas transplantation with temporary deceased donor spleen between November 2020 and January 2022. RESULTS Pre-splenic transplant, 4 sensitized patients were both T-cell and B-cell FXM positive; one was only B-cell FXM positive and 3 were DSA positive/FXM negative. Post-splenic transplant, all were FXM negative. Pre-splenic transplant class I and class II DSA were detected in 3 patients, only class I DSA in 4 patients, and only class II DSA in 1 patient. Postsplenic transplant, class I DSA was eliminated in all patients. Class II DSA persisted in 3 patients; all showed a marked decrease in DSA mean fluorescence index. Class II DSA was eliminated in one patient. CONCLUSION Donor spleen functions as a DSA graveyard and provides an immunologically safe window for kidney-pancreas transplantation.
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Affiliation(s)
| | - Sujata Gaitonde
- Department of Pathology, University of Illinois at Chicago, Illinois.
| | - Mario Spaggiari
- Department of Surgery, University of Illinois at Chicago, Illinois
| | - Alberto Fratti
- Department of Surgery, University of Illinois at Chicago, Illinois
| | | | | | - Bentio T Valdenepas
- Department of Pharmacy Practice, University of Illinois at Chicago, Illinois
| | - Priyanka Gupta
- Department of Pathology, University of Illinois at Chicago, Illinois
| | - Enrico Benedetti
- Department of Surgery, University of Illinois at Chicago, Illinois
| | - Ivo Tzvetanov
- Department of Surgery, University of Illinois at Chicago, Illinois
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15
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Frutos MÁ, Crespo M, Valentín MDLO, Alonso-Melgar Á, Alonso J, Fernández C, García-Erauzkin G, González E, González-Rinne AM, Guirado L, Gutiérrez-Dalmau A, Huguet J, Moral JLLD, Musquera M, Paredes D, Redondo D, Revuelta I, Hofstadt CJVD, Alcaraz A, Alonso-Hernández Á, Alonso M, Bernabeu P, Bernal G, Breda A, Cabello M, Caro-Oleas JL, Cid J, Diekmann F, Espinosa L, Facundo C, García M, Gil-Vernet S, Lozano M, Mahillo B, Martínez MJ, Miranda B, Oppenheimer F, Palou E, Pérez-Saez MJ, Peri L, Rodríguez O, Santiago C, Tabernero G, Hernández D, Domínguez-Gil B, Pascual J. Recommendations for living donor kidney transplantation. Nefrologia 2022; 42 Suppl 2:5-132. [PMID: 36503720 DOI: 10.1016/j.nefroe.2022.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 06/17/2023] Open
Abstract
This Guide for Living Donor Kidney Transplantation (LDKT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes. Moreover, the role of living donors in the current KT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDKT, offer additional ways to treat renal patients with an incompatible donor. Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations. This Guide does not forget that LDKT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors' health. This aspect always has to be taken into account by LDKT programmes when evaluating potential donors. Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees.
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Affiliation(s)
| | - Marta Crespo
- Nephrology Department, Hospital del Mar, Barcelona, Spain
| | | | | | - Juana Alonso
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | | | - Esther González
- Nephrology Department, Hospital Universitario 12 Octubre, Spain
| | | | - Lluis Guirado
- Nephrology Department, Fundacio Puigvert, Barcelona, Spain
| | | | - Jorge Huguet
- RT Surgical Team, Fundació Puigvert, Barcelona, Spain
| | | | - Mireia Musquera
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | - David Paredes
- Donation and Transplantation Coordination Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Ignacio Revuelta
- Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Antonio Alcaraz
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Manuel Alonso
- Regional Transplantation Coordination, Seville, Spain
| | | | - Gabriel Bernal
- Nephrology Department, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Alberto Breda
- RT Surgical Team, Fundació Puigvert, Barcelona, Spain
| | - Mercedes Cabello
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | - Joan Cid
- Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Fritz Diekmann
- Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Laura Espinosa
- Paediatric Nephrology Department, Hospital La Paz, Madrid, Spain
| | - Carme Facundo
- Nephrology Department, Fundacio Puigvert, Barcelona, Spain
| | | | | | - Miquel Lozano
- Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | | | | | | | - Eduard Palou
- Immunology Department, Hospital Clinic i Universitari, Barcelona, Spain
| | | | - Lluis Peri
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | | | | | - Domingo Hernández
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | - Julio Pascual
- Nephrology Department, Hospital del Mar, Barcelona, Spain.
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16
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Liwski RS, Tafulo S, Carroll R, Lan JH, Greenshields AL. Cutting through the weeds: Evaluation of a novel adsorption with crossmatch cells and elution protocol to sharpen HLA antibody identification by the single antigen bead assay. Front Genet 2022; 13:1059650. [PMID: 36531234 PMCID: PMC9748275 DOI: 10.3389/fgene.2022.1059650] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 11/18/2022] [Indexed: 10/01/2023] Open
Abstract
The single antigen bead (SAB) assay is the most used test for the identification of HLA specific antibodies pre- and post-transplant. Nevertheless, detection of spurious reactivities remains a recognized assay limitation. In addition, the presence of weak reactivity patterns can complicate unacceptable antigen assignment. This work presents the evaluation of the adsorption with crossmatch cells and elution (AXE) technique, which was designed to help differentiate weak HLA specific antibodies targeting native antigens from spurious and background SAB assay reactivity. The AXE protocol uses selected donor cells to adsorb HLA specific antibodies from sera of interest. Bound antibodies are then eluted off washed cells and identified using the SAB assay. Only antibodies targeting native HLA are adsorbed. Assay evaluation was performed using five cell donors and pooled positive control serum. AXE efficiency was determined by comparing SAB reactivity of adsorbed/eluted antibody to that of the antibodies in unadsorbed sera. A robust efficiency was seen across a wide range of original MFI for donor specific antibodies (DSA). A higher absorption/elution recovery was observed for HLA class I antigens vs. class II. Locus-specific variation was also observed, with high-expression HLA loci (HLA-A/B/DR) providing the best recovery. Importantly, negligible reactivity was detected in the last wash control, confirming that AXE eluates were not contaminated with HLA antibody carry-over. Donor cells incubated with autologous and DSA-containing allogeneic sera showed that AXE selectively adsorbed HLA antibodies in a donor antigen-specific manner. Importantly, antibodies targeting denatured epitopes or other non-HLA antigens were not detected by AXE. AXE was particularly effective at distinguishing weak HLA antibodies from background reactivity. When combined with epitope analysis, AXE enhanced precise identification of antibody-targeted eplets and even facilitated the characterization of a potential novel eplet. Comparison of AXE to flow cytometric crossmatching further revealed that AXE was a more sensitive technique in the detection of weak DSA. Spurious reactivities on the current SAB assay have a deleterious impact on the assignment of clinically relevant HLA specificities. The AXE protocol is a novel test that enables users to interrogate reactive patterns of interest and discriminate HLA specific antibodies from spurious reactivity.
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Affiliation(s)
- Robert S. Liwski
- Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, NS, Canada
| | - Sandra Tafulo
- Blood and Transplantation Center of Porto, Portuguese Institute for Blood and Transplantation, Porto, Portugal
| | - Robert Carroll
- Health and Medical Sciences, University of South Australia, Adelaide, SA, Australia
- Transplantation and Immunogenetics Service, Australian Red Cross Blood Services, Adelaide, SA, Australia
| | - James H. Lan
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Anna L. Greenshields
- Department of Pathology and Laboratory Medicine, Dalhousie University, Halifax, NS, Canada
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17
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Rodriguez-Ramirez S, Al Jurdi A, Konvalinka A, Riella LV. Antibody-mediated rejection: prevention, monitoring and treatment dilemmas. Curr Opin Organ Transplant 2022; 27:405-414. [PMID: 35950887 PMCID: PMC9475491 DOI: 10.1097/mot.0000000000001011] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW Antibody-mediated rejection (AMR) has emerged as the leading cause of late graft loss in kidney transplant recipients. Donor-specific antibodies are an independent risk factor for AMR and graft loss. However, not all donor-specific antibodies are pathogenic. AMR treatment is heterogeneous due to the lack of robust trials to support clinical decisions. This review provides an overview and comments on practical but relevant dilemmas physicians experience in managing kidney transplant recipients with AMR. RECENT FINDINGS Active AMR with donor-specific antibodies may be treated with plasmapheresis, intravenous immunoglobulin and corticosteroids with additional therapies considered on a case-by-case basis. On the contrary, no treatment has been shown to be effective against chronic active AMR. Various biomarkers and prediction models to assess the individual risk of graft failure and response to rejection treatment show promise. SUMMARY The ability to personalize management for a given kidney transplant recipient and identify treatments that will improve their long-term outcome remains a critical unmet need. Earlier identification of AMR with noninvasive biomarkers and prediction models to assess the individual risk of graft failure should be considered. Enrolling patients with AMR in clinical trials to assess novel therapeutic agents is highly encouraged.
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Affiliation(s)
- Sonia Rodriguez-Ramirez
- Department of Medicine, Division of Nephrology
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
| | - Ayman Al Jurdi
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ana Konvalinka
- Department of Medicine, Division of Nephrology
- Ajmera Transplant Centre, University Health Network, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network
- Institute of Medical Science, University of Toronto
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Leonardo V. Riella
- Division of Nephrology, Massachusetts General Hospital, Harvard Medical School
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
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18
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Heinemann FM, Lindemann M, Keles D, Witzke O, Kribben A, Baba HA, Becker JU, Heinold A, Horn PA, Eisenberger U. Cumulative mean fluorescent intensities of
HLA
specific antibodies predict antibody mediated rejections after kidney transplantation. HLA 2022; 100:553-562. [DOI: 10.1111/tan.14790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Falko Markus Heinemann
- Institute for Transfusion Medicine University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Monika Lindemann
- Institute for Transfusion Medicine University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Deniz Keles
- Institute for Transfusion Medicine University Duisburg‐Essen, University Hospital Essen Essen Germany
- Department of Nephrology University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Oliver Witzke
- Department of Infectious Diseases, West German Centre for Infectious Diseases University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Andreas Kribben
- Department of Nephrology University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Hideo Andreas Baba
- Institute of Pathology University Duisburg‐Essen, University Hospital Essen Essen Germany
| | | | - Andreas Heinold
- Institute for Transfusion Medicine University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Peter Alexander Horn
- Institute for Transfusion Medicine University Duisburg‐Essen, University Hospital Essen Essen Germany
| | - Ute Eisenberger
- Department of Nephrology University Duisburg‐Essen, University Hospital Essen Essen Germany
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19
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Aziz F, Parajuli S, Jorgenson M, Garg N, Manchala V, Yousif E, Mandelbrot D, Hidalgo L, Mohamed M, Zhong W, Djamali A. Chronic Active Antibody-mediated Rejection in Kidney Transplant Recipients: Treatment Response Rates and Value of Early Surveillance Biopsies. Transplant Direct 2022; 8:e1360. [PMID: 35935024 PMCID: PMC9355109 DOI: 10.1097/txd.0000000000001360] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 06/25/2022] [Indexed: 11/02/2022] Open
Abstract
UNLABELLED There is limited information on the value of short-term invasive and noninvasive monitoring in kidney transplant recipients (KTR) undergoing therapy for chronic active antibody-mediated rejection (cAMR). METHODS We describe response rates in patients with cAMR receiving pulse steroids/IVIG ± rituximab 3-mo after index biopsy. RESULTS The study included 82 consecutive KTR. Mean time from transplant to cAMR was 10 y. Mean peritubular capillaritis (ptc), glomerulitis (g), microvascular inflammation (MVI), C4d, and cg Banff scores were 1.1, 2.1, 3.2, 0.2, and 2, respectively. Mean estimated glomerular filtration rate (eGFR) and urine protein creatinine (UPC) ratio were 38 mL/min and 1.6 g/g, respectively. Thirty (37%) patients lost their allograft during the mean follow-up of 2.4 y. In patients treated with pulse steroids/IVIG (n = 41), response rates for eGFR, UPC, donor-specific antibodies (DSAs), and MVI were 27%, 49%, 7%, and 19%, respectively. In the pulse steroids/IVIG/rituximab group, response rates were 66%, 61%, 20%, and 69%, respectively. Univariate analysis identified response in eGFR (HR = 0.03; P = 0.001; 95% CI, 0.004-0.26), UPC (HR = 0.38; P = 0.01; 95% CI, 0.18-0.82), and DSA (HR = 0.11; P = 0.004; 95% CI, 0.02-0.49) as predictors of graft survival. Multivariate analysis only retained eGFR response (HR = 0.12; P = 0.01; 95% CI, 0.02-0.64). CONCLUSIONS In cAMR, short-term response to treatment for kidney function and DSA was associated with graft survival, but the role of early surveillance biopsies needs further evaluation.
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Affiliation(s)
- Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Margaret Jorgenson
- Department of Pharmacy, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Venkata Manchala
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Elsadiq Yousif
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Didier Mandelbrot
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Luis Hidalgo
- HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Maha Mohamed
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weixiong Zhong
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Arjang Djamali
- Department of Medicine, Maine Medical Center, Portland, ME
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20
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Olszowska-Zaremba N, Gozdowska J, Zagożdżon R. Clinical significance of low pre-transplant donor specific antibodies (DSA) in living donor kidney recipients with negative complement-dependent cytotoxicity crossmatches (CDCXM), and negative flow cytometry crossmatches (FLXM) - A single-center experience. Transpl Immunol 2022; 74:101672. [PMID: 35868613 DOI: 10.1016/j.trim.2022.101672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND It is controversial whether all donor-specific antibodies (DSA) detected by the solid-phase single antigen bead (SAB) assay negatively affect kidney transplantation outcomes. The study aimed to evaluate the possible clinical significance of low pre-transplant DSA in living donor kidney recipients. We analyzed a group of patients with HLA-A, B, and -DR DSA reactivities below a virtual crossmatch (VXM) value of 5000 MFI but with all VXM DSA reactivities at HLA-DQ, -DP, and -Cw, which were not typed routinely for donors prior to transplantation. We also investigated the incidence of persistent and de novo DSAs in available posttransplant SAB assays. METHODS From the historical cohort of living donor recipients transplanted between 2014 and 2018 at our center (n = 82), 55 patients met the inclusion criteria, namely: these patients were > 18 years old with non-HLA identical sibling donors, who were not desensitized, who had available pre-transplant SAB results, and who had negative both complement-dependent cytotoxicity crossmatch (CDCXM) and flow cytometry crossmatch (FLXM) results. An additional donor HLA typing, performed for all 55 recipients, identified donor additional HLA-DQ, -DP, and -Cw DSA reactivities. These patients were then divided by SAB reactivity into three groups: 1) those with DSA-positive reactivities; 2) those with non-donor-specific anti-HLA reactivities (NDSA); and, 3) those who were anti-HLA-negative. All these recipients were followed for three years and checked for their de novo or persistent DSA. RESULTS In the studied cohort, DSA-positive, NDSA reactive, and anti-HLA negative recipients constituted 33%, 36%, and 31% of 55 patients, respectively. Non-routinely considered pre-transplant HLA-DQ, -DP, and -Cw DSA-positive reactivities were shown in as many as 78% of DSA-positive cases (group 1) with the lowest MFI value of 319 to DP4 and the highest MFI of 5767 to DQ2. Of the pre-transplant HLA-A, B, and -DR DSA reactivities, only -DR52 DSA reactivity reached the highest MFI value of 2191. These detected DSAs did not reduce the mean estimated glomerular filtration rate (eGFR) values and did not increase the incidence of proteinuria in recipients. While the 3-year graft survival was lower in the DSA-positive group (94.4%) with one recipient who lost kidney transplant, the difference was not significantly different (p = 0.7) from the NDSA (100%) and negative (100%) groups. In terms of the incidence of de novo acute antibody-mediated rejection (AMR) at three years after transplantation, no case has been reported in the cohort. This may suggest that low DSA-positive recipients do not experience higher rejection rate. However, DSA-positive recipients had a tendency for a higher frequency of C4d deposits in peritubular capillaries (PTC) and de novo DSA. CONCLUSION Our 3-year follow-up of patients with low pre-transplant DSA found no association with a deterioration in graft function and worse graft survival. Furthermore, we did not observe an increase in AMR in our patients with low DSA. A larger cohort and a longer follow-up period may be needed to evaluate the tendency of low DSA-positive recipients towards the higher incidence of C4d deposits in PTC and/or de novo DSA.
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Affiliation(s)
- Natasza Olszowska-Zaremba
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland.
| | - Jolanta Gozdowska
- Department of Transplantation Medicine, Nephrology and Internal Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland.
| | - Radosław Zagożdżon
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; Department of Immunology, Transplantology and Internal Medicine, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland.
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21
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Suhail SM. Tolerance protocol of living kidney transplant for developing countries through basic strategy of lymphocyte depletion. World J Transplant 2022; 12:112-119. [PMID: 35979538 PMCID: PMC9258266 DOI: 10.5500/wjt.v12.i6.112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/28/2021] [Accepted: 05/07/2022] [Indexed: 02/06/2023] Open
Abstract
End-stage kidney failure (ESKD) is a global issue where kidney replacement therapy imposes enormous economic burden to people of developing countries, in addition to the severe limitations to the availability of hemodialysis and peritoneal dialysis technique. The best option of kidney transplantation also requires lifelong combination immunosuppressive medicines, the cost of which is equally comparable to lifelong dialysis. A strategy of achieving transplant tolerance that requires minimum immunosuppressive medicines, although in experimental stage, also requires state-of-art technology with costly medicines and interventions. This is evidently beyond the reach of ESKD patients of developing countries. Hence, globally in developing countries, a need for an innovative but cost-effective tolerance protocol is a burning need for a successful transplant program. In brief, transplant tolerance is defined as a state of donor-specific unresponsiveness to the allograft antigens without the need for ongoing pharmacologic immunosuppression or with a minimal need. Current state-of-art techniques involves: (1) A state of hematological chimera, for complete tolerance; (2) Prope or partial tolerance where immune-reactive T-lymphocytes are inhibited using monoclonal antibodies; and (3) Chimeric antigen receptor for T-regulatory (T-reg) cell therapy using genetically engineered T-reg cells targeting specific T-lymphocyte receptors for inducing anergy. From our real-world experience in transplant management in post-transplant lympho-proliferative disorders (PTLD), we noticed frequently a drastic reduction in the need of immunosuppressive medicines following lympho-ablative therapy for PTLD. We recently published a case study on a real-world experience transplant case where we explained a partial or prope tolerance that developed after lymphocyte ablation therapy, following which the allograft was maintained with low dose dual standard immunosuppressive medicines. Based on this publication, we propose here an innovative tolerance protocol for living related low risk kidney transplantation for developing countries, in this opinion review.
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Affiliation(s)
- Sufi M Suhail
- Department of Renal Medicine, Singapore General Hospital, Singapore 169856, Singapore
- Department of Clinical Research, Duke-NUS Graduate Medical School, Singapore 169856, Singapore
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22
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Recomendaciones para el trasplante renal de donante vivo. Nefrologia 2022. [DOI: 10.1016/j.nefro.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Norin AJ, Das B, Mondragon-Escorpizo MO, Bajaj H, Sumrani N, John D, Salifu MO. Determination of unacceptable antigens by summation of anti-HLA eplet antibody strength (MFI) based on single antigen bead assays: Excellent correlation with negative cell based cross matches. Hum Immunol 2022; 83:482-493. [DOI: 10.1016/j.humimm.2022.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 04/08/2022] [Accepted: 04/13/2022] [Indexed: 11/04/2022]
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Risk Factors of Rejection in Renal Transplant Recipients: A Narrative Review. J Clin Med 2022; 11:jcm11051392. [PMID: 35268482 PMCID: PMC8911293 DOI: 10.3390/jcm11051392] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple factors influence graft rejection after kidney transplantation. Pre-operative factors affecting graft function and survival include donor and recipient characteristics such as age, gender, race, and immunologic compatibility. In addition, several peri- and post-operative parameters affect graft function and rejection, such as cold and warm ischemia times, and post-operative immunosuppressive treatment. Exposure to non-self-human leucocyte antigens (HLAs) prior to transplantation up-regulates the recipient’s immune system. A higher rate of acute rejection is observed in transplant recipients with a history of pregnancies or significant exposure to blood products because these patients have higher panel reactive antibody (PRA) levels. Identifying these risk factors will help physicians to reduce the risk of allograft rejection, thereby promoting graft survival. In the current review, we summarize the existing literature on donor- and recipient-related risk factors of graft rejection and graft loss following kidney transplantation.
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25
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Shanmugham S, Prasad N, Kaul A, Bhadauria D, Patel M, Yaccha M, Kushwaha R, Behera M, Agarwal V, Srivastava A. Evanescing renal allograft cortical necrosis from living donor renal transplantation: A lesson learned over two decades. Transpl Immunol 2022; 71:101558. [PMID: 35217167 DOI: 10.1016/j.trim.2022.101558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 02/13/2022] [Accepted: 02/19/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND Renal graft cortical necrosis (GCN) is a catastrophic cause of graft failure. We evaluated the incidence, causes, management, and outcome of GCN across two decades from our center. METHODS This is a retrospective analysis of transplant patients who had biopsy-proven GCN transplanted between 2000 and 2020. The clinical details, immunological workup, induction, maintenance regimen, causes of cortical necrosis, and the outcomes were compared between the first period 2000-2012, and the second period 2013-2020, when Flow cytometric and Luminex based crossmatch were included in the workup plan. RESULTS Among 2333 live ABO-compatible renal transplants, 37 (0.015%) patients (36 patients between 2000 and 2012 and 1 between 2013 and 2020) developed GCN (60% had diffuse and 40% patchy GCN) at a median of 8 days after transplantation.Twenty-six (60%) received ATG, 4 received plasmapheresis, and ATG (10.8%) as antirejection therapy. The cyclosporine-based regimen was associated with a higher risk of GCN (RR 2.54; 95% CI 1.26 to 5.12, p = 0.009), whereas tacrolimus-based therapy had a lower risk (RR 0.39; 95% CI 0.19 to 0.79, p = 0.009). The introduction of flow cytometry and DSA assay has significantly decreased the incidence of acute rejection and GCN. Only one patient had GCN during the 2013-2020 period because of graft's mucormycosis. Twenty-five (67.56%) patients had no recovery, and 12 (32.43%) had partial recovery of graft function. CONCLUSION GCN is mainly associated with rejection, and cyclosporin-based maintenance regimen had a higher incidence. The remarkable decrease in GCN after 2013 onwards could be attributed to the use of Flowcytometry, Luminex-based DSA assays, and tacrolimus-based regimens.
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Affiliation(s)
- Sabarinath Shanmugham
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Anupama Kaul
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Dharmendra Bhadauria
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Manas Patel
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Monika Yaccha
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ravi Kushwaha
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Manas Behera
- Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Vinita Agarwal
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Aneesh Srivastava
- Department of Urology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Osickova K, Hruba P, Kabrtova K, Klema J, Maluskova J, Slavcev A, Slatinska J, Marada T, Böhmig GA, Viklicky O. Predictive Potential of Flow Cytometry Crossmatching in Deceased Donor Kidney Transplant Recipients Subjected to Peritransplant Desensitization. Front Med (Lausanne) 2022; 8:780636. [PMID: 34970564 PMCID: PMC8712553 DOI: 10.3389/fmed.2021.780636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/15/2021] [Indexed: 11/17/2022] Open
Abstract
Recipient sensitization is a major risk factor of antibody-mediated rejection (ABMR) and inferior graft survival. The predictive effect of solid-phase human leukocyte antigen antibody testing and flow cytometry crossmatch (FCXM) in the era of peritransplant desensitization remains poorly understood. This observational retrospective single-center study with 108 donor-specific antibody (DSA)-positive deceased donor kidney allograft recipients who had undergone peritransplant desensitization aimed to analyze variables affecting graft outcome. ABMR rates were highest among patients with positive pretransplant FCXM vs. FCXM-negative (76 vs. 18.7%, p < 0.001) and with donor-specific antibody mean fluorescence intensity (DSA MFI) > 5,000 vs. <5,000 (54.5 vs. 28%, p = 0.01) despite desensitization. In univariable Cox regression, FCXM positivity, retransplantation, recipient gender, immunodominant DSA MFI, DSA number, and peak panel reactive antibodies were found to be associated with ABMR occurrence. In multivariable Cox regression adjusted for desensitization treatment (AUC = 0.810), only FCXM positivity (HR = 4.6, p = 0.001) and DSA number (HR = 1.47, p = 0.039) remained significant. In conclusion, our data suggest that pretransplant FCXM and DSA number, but not DSA MFI, are independent predictors of ABMR in patients who received peritransplant desensitization.
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Affiliation(s)
- Klara Osickova
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Katerina Kabrtova
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Jiri Klema
- Department of Computer Science, Faculty of Electrical Engineering, Czech Technical University, Prague, Czechia
| | - Jana Maluskova
- Department of Pathology, Institute for Clinical and Experimental Medicine, Prague, Czechia.,Aesculab Pathology, Prague, Czechia
| | - Antonij Slavcev
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Janka Slatinska
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Tomas Marada
- Department of Transplant Surgery, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University Vienna, Vienna, Austria
| | - Ondrej Viklicky
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czechia
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27
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Shi QS, Li DH, Wu CY, Liu DZ, Hu J, Cui YL, Zhao N, Chen L, Askar M. Effects of serum from mismatched patients with solid organ transplantation on the activation of microvascular cultures isolated from adipose tissues. Transpl Immunol 2021; 69:101462. [PMID: 34508853 DOI: 10.1016/j.trim.2021.101462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/26/2021] [Accepted: 09/01/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Aggregating the human leukocyte antigen (HLA) Class I antigens on the endothelial membrane has been known to elicit an activation, an underlying mechanism of chronic rejection in organ transplant recipients. The current study aims at examining the endothelial responses using HLA typed microvascular cultures from human adipose tissues upon exposure to the serum that contain corresponding antibodies collected from mismatched transplant recipients. METHODS We have successfully cultured 30 microvascular cultures and typed their HLAs. They are functionally competent to respond to inflammatory TNF-α stimulation and the aggregating monoclonal antibody against HLA Class I. The post-transplantation serum was collected either from the recipients with pathologically diagnosed chronic rejection or from the recipients without rejection. We determined their activation either by double-staining the endothelial cells in crude cultures with flow cytometry or by quantifying cytokine releases in purified endothelial cells using ELISA. RESULTS Under our current protocol, adipose tissue cultures are functionally intact in regard to its responses to TNF-alpha and anti-HLA Class I antibody. We observed that the post-transplantation serum with rejection contained the pathogenic antibodies and led to proinflammatory activation, as demonstrated by not only increased CD54+/CD31+ and CD106+/CD31+ cell counts but also inflammatory cytokine releases including MCP-1, IL-8 and RANTES. CONCLUSION This methodological study provides the feasibility of examining the pathogenicity of the alloantibodies in mis-transplant serum. Potentially, the endothelial activation elicited as a result of exposure can be used as an alternative readout for chronic rejection. SIGNIFICANCE We prototype an ex vivo model that enables us to examine whether allogenic antibodies from the recipient can functionally activate microvascular endothelial cells from the donor adipose tissues. This system can be further developed as crossmatch using cellular responses as readouts for chronic rejection for post-transplant surveillance.
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Affiliation(s)
- Qiang Sebastian Shi
- Minnie & Max T. Voelcker Laboratory, Tianjin International Joint Academy of Biomedicine, S1515 Room, 220 Dongting Road, TEDA, Tianjin, China; Minnie & Max T. Voelcker Laboratory LLC, 1120 Piedmont Lane, Richardson, TX 75080, USA.
| | - Dai-Hong Li
- Transplant Unit, Department of Blood Bank, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, China
| | - Cheng-Yu Wu
- Transplant Immunology Laboratory, Central Texas Baylor Scott & White Health, 2401 South 31st Street, Temple, TX 76508, United States of America.
| | - Da-Zhen Liu
- Department of Urology, General Hospital, Tianjin Medical University, 154 Anshan Street, Heping District, Tianjin, China
| | - Jun Hu
- Department of Colorectal Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Hexi District, Tianjin 300060, China.
| | - Yun-Long Cui
- Department of Colorectal Cancer Surgery, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Hexi District, Tianjin 300060, China
| | - Na Zhao
- Minnie & Max T. Voelcker Laboratory, Tianjin International Joint Academy of Biomedicine, S1515 Room, 220 Dongting Road, TEDA, Tianjin, China; Minnie & Max T. Voelcker Laboratory LLC, 1120 Piedmont Lane, Richardson, TX 75080, USA
| | - Li Chen
- Transplant Unit, Department of Blood Bank, Tianjin First Central Hospital, 24 Fukang Road, Nankai District, Tianjin, China; Minnie & Max T. Voelcker Laboratory LLC, 1120 Piedmont Lane, Richardson, TX 75080, USA
| | - Medhat Askar
- Transplant Immunology, Baylor University Medical Center, 3500 Gaston Ave, 4th Floor of the Y Wing, RM# L-0470, Dallas, TX 75246, United States of America.
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Rosser C, Sage D. Approaches for the characterization of clinically relevant pre-transplant human leucocyte antigen (HLA) antibodies in solid organ transplant patients. Int J Immunogenet 2021; 48:385-402. [PMID: 34346180 DOI: 10.1111/iji.12552] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/30/2021] [Accepted: 07/22/2021] [Indexed: 11/27/2022]
Abstract
The avoidance of antibody-mediated rejection (AMR) attributed to human leucocyte antigen (HLA) antibody incompatibility remains an essential function of clinical Histocompatibility and Immunogenetics (H&I) laboratories who are supporting solid organ transplantation. Developments in HLA antibody identification assays over the past thirty years have greatly reduced unexpected positive cellular crossmatches and improved solid organ transplant outcomes. For sensitized patients, the decision to register unacceptable HLA antigen mismatches is often heavily influenced by results from solid phase antibody assays, particularly the Luminex® Single Antigen Bead (SAB) assays, although the clinical relevance of antibodies identified solely by these assays remains unclear. As such, the identification of non-clinically relevant antibodies may proportionally increase the number of unacceptable transplant mismatches registered, with an associated increase in waiting time for a compatible organ. We reflect on the clinical relevance of antibodies identified solely by the Luminex SAB® assays and consider whether the application of additional assays and/or tools could further develop our ability to define the clinical relevance of antibodies identified in patient sera. Improvements in this area would assist equity of access to a compatible transplant for highly sensitized patients awaiting a solid organ transplant.
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Affiliation(s)
- Carla Rosser
- NHS Blood and Transplant (Tooting), Histocompatibility and Immunogenetics, London, UK
| | - Deborah Sage
- NHS Blood and Transplant (Tooting), Histocompatibility and Immunogenetics, London, UK
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Heidt S, Haasnoot GW, van der Linden-van Oevelen MJH, Claas FHJ. Highly Sensitized Patients Are Well Served by Receiving a Compatible Organ Offer Based on Acceptable Mismatches. Front Immunol 2021; 12:687254. [PMID: 34248971 PMCID: PMC8267476 DOI: 10.3389/fimmu.2021.687254] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 06/14/2021] [Indexed: 01/10/2023] Open
Abstract
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 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.
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Affiliation(s)
- Sebastiaan Heidt
- Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | - Geert W Haasnoot
- Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | | | - Frans H J Claas
- Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
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30
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Liu W, Zhao J, Kang ZY, Xiao YL, Yang L, Liu C, Li DH. De novo donor-specific HLA antibodies reduce graft survival rates and increase the risk of kidney transplant rejection: A single-center retrospective study. Transpl Immunol 2021; 68:101430. [PMID: 34147608 DOI: 10.1016/j.trim.2021.101430] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND We investigated the impact of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) on long-term death-censored graft survival and renal allograft rejection in kidney transplant recipients. METHODS The sample for this retrospective cohort study comprised 121 recipients of kidney transplants with negative complement-dependent cytotoxicity crossmatches to their deceased donors. Recipients were divided into two groups: dnDSAs+ (n = 31) and dnDSAs- (n = 90). We evaluated rejection and long-term graft survival rates in the recipients along with pathologic changes in the transplanted kidneys. RESULTS DnDSAs were identified in 31/121 patients (25.6%). The graft survival rate in the dnDSAs+ group was 87.1% (27/31) and that of the dnDSAs- group was 97.8% (88/90). The dnDSAs+ group had lower graft survival rates than patients without dnDSAs (p = 0.007). There was no difference in the graft survival rates between patients with high DSA mean fluorescence intensity (≥4000) and those with low intensity (<4000) (p = 0.669). There was also no difference in the graft survival rates of patients with HLA class I, II, and I + II dnDSAs (p = 0.571). The presence of dnDSA in serum was associated with a higher incidence of antibody- and T-cell-mediated rejection (p < 0.0001). Banff scores for arterial fibrointimal and arteriolar hyalin, thickening as well as C4d deposition differed for the dnDSAs+ and dnDSAs- groups (p < 0.05). CONCLUSION DnDSAs were found to be associated with decreased long-term graft survival rates and increased rejection rates, often accompanied by C4d deposition.
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Affiliation(s)
- Wei Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Jie Zhao
- Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Zhong-Yu Kang
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Yan-Li Xiao
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Li Yang
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Chun Liu
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China
| | - Dai-Hong Li
- Department of Blood Transfusion, Tianjin First Central Hospital, Tianjin, China.
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Schmitz R, Fitch ZW, Schroder PM, Choi AY, Jackson AM, Knechtle SJ, Kwun J. B cells in transplant tolerance and rejection: friends or foes? Transpl Int 2021; 33:30-40. [PMID: 31705678 DOI: 10.1111/tri.13549] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/21/2019] [Accepted: 11/04/2019] [Indexed: 12/14/2022]
Abstract
Our understanding of the role of B cells in organ transplantation remains incomplete and continues to grow. The majority of research has focused on the detrimental role of antibodies that drive the development of pathogenesis of the transplanted organ. However, it has been shown that not all donor-specific antibodies are harmful and in some circumstances can even promote tolerance through the mechanism of accommodation. Furthermore, B cells can have effects on transplanted organs through their interaction with T cells, namely antigen presentation, cytokine production, and costimulation. More recently, the role and importance of Bregs was introduced to the field of transplantation. Due to this functional and ontogenetic heterogeneity, targeting B cells in transplantation may bring undesired immunologic side effects including increased rejection. Therefore, the selective control of B cells that contribute to the humoral response against donor antigens will continue to be an important and challenging area of research and potentially lead to improved long-term transplant outcomes.
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Affiliation(s)
- Robin Schmitz
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Zachary W Fitch
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Paul M Schroder
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Ashley Y Choi
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Annette M Jackson
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Stuart J Knechtle
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
| | - Jean Kwun
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, NC, USA
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32
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Reducing Donor-specific Antibody During Acute Rejection Diminishes Long-term Renal Allograft Loss: Comparison of Early and Late Rejection. Transplantation 2021; 104:2403-2414. [PMID: 32000256 DOI: 10.1097/tp.0000000000003145] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Reduction in donor-specific antibody (DSA) has been associated with improved renal allograft survival after antibody-mediated rejection (AMR). These observations have not been separately analyzed for early and late AMR and mixed acute rejection (MAR). The purpose of this study was to evaluate long-term responses to proteasome inhibitor-based therapy for 4 rejection phenotypes and to determine factors that predict allograft survival. METHODS Retrospective cohort study evaluating renal transplant recipients with first AMR episodes treated with proteasome inhibitor-based therapy from January 2005 to July 2015. RESULTS A total of 108 patients were included in the analysis. Immunodominant DSA reduction at 14 days differed significantly (early AMR 79.6%, early MAR 54.7%, late AMR 23.4%, late MAR 21.1%, P < 0.001). Death-censored graft survival (DCGS) differed at 3 years postrejection (early AMR 88.3% versus early MAR 77.8% versus late AMR 56.7% versus late MAR 54.9%, P = 0.02). Multivariate analysis revealed that immunodominant DSA reduction > 50% at 14 days was associated with improved DCGS (odds ratio, 0.12, 95% CI, 0.02-0.52, P = 0.01). CONCLUSIONS In summary, significant differences exist across rejection phenotypes with respect to histological and DSA responses. The data suggest that DSA reduction may be associated with improved DCGS in both early and late AMR.
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33
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Wani A, Kaul A, Bhaduaria DS, Zahir Z, Prasad N, Gupta A, Sharma RK. Red herrings in crossmatching kidneys for transplant. SAUDI JOURNAL OF KIDNEY DISEASES AND TRANSPLANTATION 2021; 31:289-293. [PMID: 32129228 DOI: 10.4103/1319-2442.279956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Crossmatching of prospective renal transplant donors against recipients is a mandatory component of the transplant workup, being performed for over 40 years now. Allografting patients with human leukocyte antigens which are recognized by preformed antibodies constitutes the main cause of hyperacute or acute rejections. The existence of these donor-specific anti-human leukocyte antigen antibodies (DSAs) is regarded as a contraindication for graft trans-plantation, both cadaveric and live kidney. We present two unusual cases in which both complement-dependent cytotoxicity crossmatch and DSA by Luminex were falsely positive due to autoimmune and infectious causes, but single-antigen bead assay showed these antibodies to be against nondonor antigens. After treating their basic disease, thought to be responsible for false-positive DSA, these patients became DSA negative and underwent transplantation with an uneventful posttransplant period. Our aim through these examples is to highlight the problem of false-positive crossmatch in potential renal allograft transplant recipients. Further, we propose antigenic determination of donor-specific antibodies in such patients where we suspect the immune system to be chronically activated to pick up false-positive cases and therefore increase the donor pool without compromising the transplant outcome.
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Affiliation(s)
- Asif Wani
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anupma Kaul
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Dharmendra Singh Bhaduaria
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Zafirah Zahir
- Department of Pathology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Narayan Prasad
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Amit Gupta
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Raj Kumar Sharma
- Department of Nephrology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Aziz F, Tiwari A, Patel H, Chauhan R. Pretransplant histocompatibility testing algorithm: Laboratory and clinical approach in the Indian context. INDIAN JOURNAL OF TRANSPLANTATION 2021. [DOI: 10.4103/ijot.ijot_82_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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35
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Cun H, Hönger G, Kleiser M, Amico P, Wehmeier C, Steiger J, Dickenmann M, Schaub S. Screening strategy for de novo donor-specific HLA antibodies beyond the first year after kidney transplantation: Personalized or "one size fits all"? Clin Transplant 2020; 35:e14170. [PMID: 33247476 DOI: 10.1111/ctr.14170] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/18/2020] [Accepted: 11/19/2020] [Indexed: 11/28/2022]
Abstract
Screening for de novo donor-specific HLA antibodies (DSAs) after kidney transplantation is widely recommended. The aim of this single-center, cross-sectional study was to investigate the frequency of therapeutic interventions triggered by de novo DSA screening. We included 464 patients screened for de novo DSA at annual visits after a median of 5 years post-transplant (range 1 to 19 years). Overall, de novo DSAs were detected in 55/464 patients (11.9%) with a stepwise increase of the prevalence from 4.9% at 1 year post-transplant to 18.9% at >10 years post-transplant. Subsequent allograft biopsies were performed in 24/55 patients (44%). The main reasons to omit biopsies were good/stable allograft function and anticipated lack of clinical consequences (eg, relevant comorbidities). Rejection processes were detected in 16/24 biopsies (67%). Therapeutic interventions were made in 18/464 screened patients (3.9%) with a significantly higher rate in the youngest quartile of patients (≤48 years; 7.9%) compared to the middle 50% (49-67 years; 3%) and the oldest quartile (≥68 years; 1.7%) (P = .03). Our study suggests that the frequency of therapeutic interventions triggered by de novo DSA screening after kidney transplantation is overall low, but significantly higher in younger patients, arguing for a personalized, age-adapted de novo DSA screening strategy.
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Affiliation(s)
- Hasret Cun
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Gideon Hönger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.,HLA-Diagnostic and Immungenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Marc Kleiser
- HLA-Diagnostic and Immungenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Patrizia Amico
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,HLA-Diagnostic and Immungenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
| | - Caroline Wehmeier
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Michael Dickenmann
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland.,Transplantation Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.,HLA-Diagnostic and Immungenetics, Department of Laboratory Medicine, University Hospital Basel, Basel, Switzerland
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36
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Car H, Karahan GE, Dreyer GJ, Brand-Schaaf SH, de Vries APJ, van Kooten C, Kramer CSM, Roelen DL, Claas FHJ, Heidt S. Low incidence of IgA isotype of HLA antibodies in alloantigen exposed individuals. HLA 2020; 97:101-111. [PMID: 33227174 PMCID: PMC7898292 DOI: 10.1111/tan.14146] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/30/2020] [Accepted: 11/09/2020] [Indexed: 11/30/2022]
Abstract
Human leukocyte antigen (HLA) antibodies are induced by pregnancy, transfusion, or transplantation. Serum from transplant recipients is regularly screened for IgG HLA antibodies because of their clinical relevance for transplant outcome. While other isotypes of HLA antibodies, such as IgA may also contribute to the alloimmune response, validated detection assays for IgA HLA antibody detection are lacking. Therefore, we modified the commonly used luminex screening assay for IgG HLA antibody detection (IgG-LMX) into an IgA HLA antibody screening assay (IgA-LMX). Optimization and validation was performed with IgG, IgA1, and IgA2 isotype variants of HLA-specific human recombinant monoclonal antibodies (mAbs). Reactivity patterns of IgA1 and IgA2 isotype HLA-specific mAbs in IgA-LMX were identical to those of the IgG isotype. Cross-reactivity with IgG and IgM antibodies and nonspecific binding to the beads were excluded. Further assay validation showed the absence of IgA HLA antibodies in serum from individuals without alloantigen exposure (n = 18). When the IgA-LMX assay was applied to sera from 289 individuals with known alloantigen exposure through pregnancy (n = 91) or kidney transplantation (n = 198), IgA HLA antibodies were detected in 3.5% of individuals; eight patients on the kidney retransplant waitlist and two women immunized through pregnancy. The majority (90%) of IgA HLA antibodies were directed against HLA class II and were always present in conjunction with IgG HLA antibodies. Results of this study show that this validated IgA-LMX method can serve as a screening assay for IgA HLA antibodies and that the incidence of IgA HLA antibodies in alloantigen exposed individuals is low.
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Affiliation(s)
- Helena Car
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Gonca E Karahan
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Geertje J Dreyer
- Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.,Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Simone H Brand-Schaaf
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Aiko P J de Vries
- Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.,Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Cees van Kooten
- Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands.,Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Cynthia S M Kramer
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Dave L Roelen
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
| | - Frans H J Claas
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands.,Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
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Senev A, Emonds M, Van Sandt V, Lerut E, Coemans M, Sprangers B, Kuypers D, Naesens M. Clinical importance of extended second field high-resolution HLA genotyping for kidney transplantation. Am J Transplant 2020; 20:3367-3378. [PMID: 32337773 PMCID: PMC7754319 DOI: 10.1111/ajt.15938] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 04/07/2020] [Accepted: 04/08/2020] [Indexed: 01/25/2023]
Abstract
The need for extended second field high-resolution (2F-HR) HLA genotyping in kidney transplantation is debated. In a cohort of 1000 kidney transplants, we evaluated the impact of different HLA genotyping levels on the assignment of donor-specific anti-HLA antibodies (DSA) and investigated whether inference of 2F-HR genotypes from low-resolution (LR) genotypes could be used to correctly assign DSA. Based on LR genotypes, 224 pretransplant DSAs were present in 140 patients and absent in 860 patients (DSAneg group). With extended 2F-HR HLA genotyping, we confirmed 173 DSA (77.2%) in 108 (77.1%) patients (2F-HRpos LRpos DSA group) and excluded DSA in 32 patients (22.9%) (2F-HRneg LRpos DSA group). Kaplan-Meier curves showed that 10-year graft survival rates were similar between the DSAneg and 2F-HRneg LRpos DSA groups (82.4% vs 93.8%; P = .27) and confirmed that DSA determined using LR typing but not confirmed using 2F-HR typing were indeed misclassified. By inferring 2F-HR genotypes using HaploStats, DSA still could not be correctly assigned in 23.3% of cases. We conclude that extended 2F-HR typing of the donor-recipient pairs is relevant for the correct assessment of DSA. Although inference of 2F-HR genotypes may improve the assessment of DSA in some cases, significant misclassification occurs, and warrants caution in using inferred HLA results for clinical and research purposes.
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Affiliation(s)
- Aleksandar Senev
- Histocompatibility and Immunogenetics LaboratoryBelgian Red Cross‐FlandersMechelenBelgium,Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium
| | - Marie‐Paule Emonds
- Histocompatibility and Immunogenetics LaboratoryBelgian Red Cross‐FlandersMechelenBelgium,Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium
| | - Vicky Van Sandt
- Histocompatibility and Immunogenetics LaboratoryBelgian Red Cross‐FlandersMechelenBelgium
| | - Evelyne Lerut
- Department of Imaging & PathologyUniversity Hospitals LeuvenLeuvenBelgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium,Department of Nephrology and Renal TransplantationUniversity Hospitals LeuvenLeuvenBelgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium,Department of Nephrology and Renal TransplantationUniversity Hospitals LeuvenLeuvenBelgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and TransplantationKU LeuvenLeuvenBelgium,Department of Nephrology and Renal TransplantationUniversity Hospitals LeuvenLeuvenBelgium
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Good-Weber M, Roos M, Mueller TF, Rüsi B, Fehr T. Tailored immunosuppression after kidney transplantation - a single center real-life experience. BMC Nephrol 2020; 21:501. [PMID: 33228545 PMCID: PMC7686677 DOI: 10.1186/s12882-020-02137-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 10/29/2020] [Indexed: 11/30/2022] Open
Abstract
Background Kidney allograft survival continuously improved with introduction of novel immunosuppressants. However, also immunologically challenging transplants (blood group incompatibility and sensitized recipients) increase. Between 2006 and 2008, a new tailored immunosuppression scheme for kidney transplantation was implemented at the University Hospital in Zurich, together with an ABO-incompatible transplant program and systematic pre- and posttransplant anti-human leukocyte antigen (HLA) antibody screening by Luminex technology. This study retrospectively evaluated the results of this tailored immunosuppression approach with a particular focus on immunologically higher risk transplants. Methods A total of 204 consecutive kidney transplantations were analyzed, of whom 14 were ABO-incompatible and 35 recipients were donor-specific anti-HLA antibodies (DSA) positive, but complement-dependent cytotoxicity crossmatch (CDC-XM) negative. We analyzed patient and graft survival, acute rejection rates and infectious complications in ABO-compatible versus -incompatible and in DSA positive versus negative patients and compared those with a historical control group. Results Overall patient, death-censored allograft survival and non-death-censored allograft survival at 4 years were 92, 91 and 87%, respectively. We found that (1) there were no differences between ABO-compatible and -incompatible and between DSA positive and DSA negative patients concerning acute rejection rate and graft survival; (2) compared with the historical control group there was a significant decrease of acute rejection rates in sensitized patients who received an induction with thymoglobulin; (3) there was no increased rate of infection among the patients who received induction with thymoglobulin compared to no induction therapy. Conclusions We observed excellent overall mid-term patient and graft survival rates with our tailored immunosuppression approach. Induction with thymoglobulin was efficient and safe in keeping rejection rates low in DSA positive patients with a negative CDC-XM. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-020-02137-5.
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Affiliation(s)
- Miriam Good-Weber
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Malgorzata Roos
- Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University Zurich, Zurich, Switzerland
| | - Thomas F Mueller
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Barbara Rüsi
- HLA Typing Laboratory, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Fehr
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland. .,Department of Internal Medicine, Cantonal Hospital Graubünden, Loestrasse 170, 7000, Chur, Switzerland.
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Delayed Graft Function and Acute Rejection in Kidney Transplant Patients with Positive Panel-Reactive Antibody and Negative Donor-Specific Antibodies. Nephrourol Mon 2020. [DOI: 10.5812/numonthly.107969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Delayed graft function (DGF) and acute rejection (AR) are common complications in kidney transplant patients. Objectives: The study evaluated DGF and AR in highly sensitized patients and their effects on kidney function for six months post-transplantation. Methods: We enrolled 95 patients with kidney transplants from living donors who were divided into two groups. Group 1 included 47 highly sensitized patients with panel reactive antibody (PRA) < 20.0% and negative donor-specific antigen, and group 2 included 48 patients with negative PRA. All patients were followed for the state of DGF, AR, and kidney function for six months. Results: Group 1 showed a significantly higher proportion of DGF and AR than group 2 (27.7% versus 2.1%, P < 0.001 and 14.9% versus 2.1%, P = 0.031, respectively). The rates of positive PRA in DGF and AR patients were significantly higher than those in non-DGF and non-AR patients (92.9% versus 42.0%, P < 0.001 and 87.5% versus 46.0%, P = 0.031, respectively). Transplanted kidney function was significantly worse in patients with PRA and DGF and/or AR than in patients with negative PRA and non-DGF and non-AR only in the seventh-day post-transplantation. Conclusions: Kidney transplant in highly sensitized patients with positive PRA was related to the increased ratio of DGF and AR.
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40
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Donor specific anti HLA sensitization is associated with inferior short term outcome in ABO- incompatible renal transplantation. TRANSPLANTATION REPORTS 2020. [DOI: 10.1016/j.tpr.2020.100059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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41
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Association of Antibody-Secreting Cells With Allograft Rejection After Renal Transplantation. Transplant Proc 2020; 52:1729-1733. [DOI: 10.1016/j.transproceed.2019.12.059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 12/06/2019] [Indexed: 12/20/2022]
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Differential Impact of Delayed Graft Function in Deceased Donor Renal Transplant Recipients With and Without Donor-specific HLA-antibodies. Transplantation 2020; 103:e273-e280. [PMID: 31205266 DOI: 10.1097/tp.0000000000002802] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Delayed graft function (DGF) and pretransplant donor-specific HLA-antibodies (DSA) are both regarded as risk factors for rejection and lower graft survival. However, the combined impact of DGF and DSA has not been studied in detail. METHODS We investigated 375 deceased donor kidney transplantations, which had DSA assignment by single-antigen bead technology and which had surveillance biopsies at 3 of 6 months. Median follow-up time was 6.1 years. RESULTS DGF occurred in 137 of 375 patients (37%), and DSA were present in 85 of 375 patients (23%). The incidence of DGF was similar in DSA-positive (DSApos)-patients and DSA-negative (DSAneg)-patients (40% versus 36%; P = 0.45). In DSAneg-patients, 5-year graft survival was not different with/without DGF (81% versus 83%; P = 0.48). By contrast, in DSApos-patients, 5-year graft survival was significantly lower with DGF (64% versus 79%; P = 0.01). Moreover, DSApos-patients with DGF had a higher 1-year incidence of subclinical rejection, which were mostly antibody-mediated or mixed rejection phenotypes. Graft loss due to rejection was significantly more frequent in DSApos-patients with DGF (5/34; 15%) compared to DSApos-patients without DGF (2/51; 4%), and DSAneg-patients with/without DGF (3/103; 3% and 4/187; 2%, respectively) (P = 0.005). In a multivariate Cox model, DSA with DGF was an independent predictor for graft (hazard ratio = 2.84 [95% confidence interval, 1.54-5.06]; P = 0.001) and death-censored graft loss (hazard ratio = 4.65 [95% confidence interval, 1.83-11.51]; P = 0.002). CONCLUSIONS DGF has a much more detrimental impact in DSApos-patients than in DSAneg-patients, which is likely related to a higher incidence of antibody-mediated rejection. If possible, the combined risks of DGF and DSA should be avoided.
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Kolonko A, Słabiak-Błaż N, Karkoszka H, Więcek A, Piecha G. The Preliminary Results of Bortezomib Used as A Primary Treatment for An Early Acute Antibody-Mediated Rejection after Kidney Transplantation-A Single-Center Case Series. J Clin Med 2020; 9:jcm9020529. [PMID: 32075220 PMCID: PMC7074248 DOI: 10.3390/jcm9020529] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/06/2020] [Accepted: 02/12/2020] [Indexed: 01/10/2023] Open
Abstract
Proteasome inhibitor bortezomib has been used in the treatment of refractory cases of acute and chronic antibody-mediated rejection (AMR) in kidney transplant recipients. However, its efficacy and safety as a primary treatment for early AMR has been scarcely investigated. We herein present our preliminary experience with bortezomib- and plasmapheresis-based primary treatment for early AMR. Thirteen patients transplanted between October 2015 and September 2019 were treated (starting at median 19th post-transplant day) with bortezomib/plasmapheresis protocol for early biopsy-proven AMR. Twelve out of thirteen patients received 4 doses and one patient recieved 3 doses of bortezomib (1.3 mg/m2 per dose). In 11/13 patients, 4–7 concomitant plasmapheresis sessions were performed, with or without intravenous immunoglobulin (IVIG). Of note, rituximab was not used in all study patients. The kidney graft and patient survival were 100%. The mean 3-month estimated glomerular filtration rate (eGFR) was 55.3 (95%CI: 44.9–65.8) mL/min/1.73m2, 8/13 patients completed 12-month follow-up with mean eGFR 60.4 (45.4–75.4) mL/min/1.73m2, and 6/13 patients completed a 24-month follow-up period with mean eGFR 73.9 (56.7–91.1) mL/min/1.73m2. Neutropenia < 1 G/L was observed in one patient, third or fourth grade thrombocytopenia in two patients, and eleven patients needed a blood transfusion (median: 2 units/patient). The mid-term results of a primary bortezomib-based treatment for kidney AMR showed its non-inferiority as compared to preceding regimens and acceptable safety. However, our data should be validated in a multicenter randomized trial.
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Ishida H, Inui M, Yagisawa T, Yamaguchi Y, Tanabe K. Quantitative analysis of humoral immunity by flow-cytometric crossmatch using molecules of equivalent soluble fluorochromosome (FCXM-MESF). Asian J Surg 2020; 43:532-537. [PMID: 32007368 DOI: 10.1016/j.asjsur.2019.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Revised: 10/01/2019] [Accepted: 11/07/2019] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVES In this study, we examined the quantitative significance of humoral immunity by flow-cytometric crossmatch using molecules of equivalent soluble fluorochromosome (FCXM-MESF) in recipients of kidney transplantation. We stratified the recipients into four sensitization classes, from non-sensitized to strongly sensitized by the results of the FCXM-MESF assay, and compared the pathological results after transplantation by the sensitization status. MATERIALS AND METHODS We stratified 140 recipients into four groups according to their sensitization status, as follows; none/NDSA, defined by FCXM-MESF values of below the cut-off value (n = 79), mildly sensitized, defined by FCXM-MESF values of less than 3000 (N = 45); moderately sensitized, defined by FCXM-MESF values of between 3000 and 8000 (N = 12); strongly sensitized, defined by FCXM-MESF values exceeding 8000 (N = 4). RESULTS We employed tailor-made immunosuppressive regimens according to the FCXM-MESF values for the 140 recipients between 2009 and 2011. In regard to the pathological results, 4% (2/51), 3% (1/35), 20% (2/10) and 75% (3/4) of the none/Non Donor Specific Antibody (NDSA), mildly sensitized, moderately sensitized and strongly sensitized patients showed antibody mediated rejection (AMR). Thus, FCXM may be more useful for the detection of anti-non-HLA as well as for that of anti-HLA antibodies than the solid phase assay (SPA) or panel reactive antibody (PRA) assay. CONCLUSION Quantitative analysis using FCXM-MESF assay accurately reflected the clinical as well as pathological aspects, and may serve as a useful guide for the selection of appropriate anti-rejection therapy.
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Affiliation(s)
- Hideki Ishida
- Department of Urology, Tokyo Women's Medical University, Japan.
| | - Masashi Inui
- Department of Urology, Tokyo Women's Medical University, Japan
| | | | | | - Kazunari Tanabe
- Department of Urology, Tokyo Women's Medical University, Japan
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Pretransplant Donor-Specific Anti-HLA Antibodies and the Risk for Rejection-Related Graft Failure of Kidney Allografts. J Transplant 2020; 2020:5694670. [PMID: 32099669 PMCID: PMC7008278 DOI: 10.1155/2020/5694670] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/16/2019] [Indexed: 02/07/2023] Open
Abstract
Background The presence of donor-specific antibodies (DSAs) against HLA before kidney transplantation has been variably associated with decreased long-term graft survival. Data on the relation of pretransplant DSA with rejection and cause of graft failure in recipients of donor kidneys are scarce. Methods Patients transplanted between 1995 and 2005 were included and followed until 2016. Donor-specific antibodies before transplantation were determined retrospectively. For cause, renal transplant biopsies were reviewed. Results Pretransplant DSAs were found in 160 cases on a total of 734 transplantations (21.8%). In 80.5% of graft failures, a diagnostic renal biopsy was performed. The presence of pretransplant DSA (DSApos) increased the risk of graft failure within the first 3 months after transplantation (5.2% vs. 9.4%) because of rejection with intragraft thrombosis (p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos, p < 0.01). One year after transplantation, DSApos recipients had an increased hazard for antibody-mediated rejection at 10 years (9% DSAneg vs. 15% DSApos. Conclusions Pretransplant DSAs are a risk factor for early graft loss and increase the incidence for humoral rejection and graft loss but do not affect the risk for T cell-mediated rejection.
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Wang J, Wang P, Wang S, Tan J. Donor-specific HLA Antibodies in Solid Organ Transplantation: Clinical Relevance and Debates. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2019; 000:1-11. [DOI: 10.14218/erhm.2019.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Mendoza Rojas A, Hesselink DA, van Besouw NM, Baan CC, van Gelder T. Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients. Expert Rev Clin Immunol 2019; 15:1323-1331. [PMID: 31721605 DOI: 10.1080/1744666x.2020.1693263] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: De novo donor-specific antibodies (dnDSA) directed against HLA are a major contributing factor to the chronic deterioration of renal allograft function. Several factors, including the degree of HLA matching, younger recipient age, and past sensitization events have been shown to increase the risk for the development of dnDSA. The development of dnDSA is also strongly associated with modifications in the immunosuppressive regimen, non-adherence, and under-immunosuppression.Areas covered: Tacrolimus is widely used after solid organ transplantation (SOT) and in recent years, both a high intra-patient variability in tacrolimus exposure and low tacrolimus exposure have been found to be associated with a higher risk of dnDSA development in kidney transplant recipients. This article provides an overview of current findings published in the recent 5 years regarding the relationship between tacrolimus exposure and variation therein and the development of dnDSA.Expert opinion: In this review, we describe how combining data on tacrolimus intra-patient variability and mean pre-dose concentration may be an effective tool to identify kidney transplant recipients who are at higher risk of developing dnDSA.
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Affiliation(s)
- Aleixandra Mendoza Rojas
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Nicole M van Besouw
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Teun van Gelder
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
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Class and Kinetics of Weakly Reactive Pretransplant Donor-specific HLA Antibodies Predict Rejection in Kidney Transplant Recipients. Transplant Direct 2019; 5:e478. [PMID: 31576374 PMCID: PMC6708635 DOI: 10.1097/txd.0000000000000926] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Accepted: 06/19/2019] [Indexed: 11/27/2022] Open
Abstract
Background The clinical impact of weakly reactive pretransplant donor-specific antibody (DSA) in kidney transplantation is controversial. While some evidence suggests that weakly reactive DSA can lead to rejection, it is unclear which patients are at risk for rejection and whether posttransplant changes in weakly reactive DSA are clinically meaningful. Methods We retrospectively studied 80 kidney transplant recipients with weakly reactive pretransplant DSA between 2007 and 2014. We performed a multivariate Cox regression analysis to identify immunologic factors most associated with risk of biopsy-proven rejection. Results Biopsy-proven rejection occurred in 13 of 80 (16%) patients. The presence of both class I and II DSA before transplant (hazards ratio 17.4, P < 0.01) and any posttransplant increase in DSA reactivity above a mean fluorescence intensity of 3000 (hazards ratio 7.8, P < 0.01) were each significantly associated with an increased risk of rejection, which primarily occurred within the first 18 months. Conclusions Pretransplant DSA class and DSA kinetics after transplantation are useful prognostic indicators in patients with weak DSA reactivity. These results identify a small, high-risk patient group that warrants aggressive posttransplant DSA monitoring and may benefit from alternative donor selection.
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Heidt S, Haasnoot GW, Witvliet MD, van der Linden‐van Oevelen MJH, Kamburova EG, Wisse BW, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Spierings E, Hack CE, van Reekum FE, van Zuilen AD, Verhaar MC, Bots ML, Drop ACAD, Plaisier L, Seelen MAJ, Sanders J, Hepkema BG, Lambeck AJA, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens MA, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KAMI, van der Weerd NC, ten Berge IJM, Bemelman FJ, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Otten HG, Roelen DL, Claas FHJ. Allocation to highly sensitized patients based on acceptable mismatches results in low rejection rates comparable to nonsensitized patients. Am J Transplant 2019; 19:2926-2933. [PMID: 31155833 PMCID: PMC6790659 DOI: 10.1111/ajt.15486] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 05/04/2019] [Accepted: 05/08/2019] [Indexed: 01/25/2023]
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 HLA-DR, or 2 HLA-DR 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.
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Fujiyama N, Satoh S, Saito M, Numakura K, Inoue T, Yamamoto R, Saito T, Kanda S, Narita S, Mitobe Y, Habuchi T. Impact of persistent preformed and de novo donor-specific antibodies detected at 1 year after kidney transplantation on long-term graft survival in Japan: a retrospective study. Clin Exp Nephrol 2019; 23:1398-1406. [PMID: 31493185 DOI: 10.1007/s10157-019-01780-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 08/09/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND We evaluated the impact of persistent preformed donor-specific antibody (DSA) and de novo DSA (dnDSA) detected at 1 year posttransplantation on long-term death-censored graft survival. METHODS One hundred and sixty adult patients who received living kidney allograft with pretransplant-negative T-cell complement-dependent cytotoxicity crossmatch (CDCXM), and without periodic screening for DSA, were eligible for this study. All enrolled patients were retrospectively tested for DSA using the Luminex assay. The presence of DSA was analyzed in stored serum samples collected at 1 year posttransplantation. If the recipients had DSA, it was analyzed in the pretransplant serum sample. The detection of DSA solely in the 1 year posttransplant sample was defined as dnDSA, and DSA detection in both pretransplant and 1 year posttransplant samples was defined as persistent preformed DSA. RESULTS DSAs were identified in 14 (8.8%) of the 160 patients. Seven patients had persistent preformed DSA, 6 had dnDSA, and 1 had both persistent preformed and dnDSA at 1 year posttransplantation. Death-censored allograft survival rates of patients with DSA versus those without DSA at 7 and 11 years were 77.9 vs. 97.8% and 60.6 vs. 89.2%, respectively. The graft survival rate was lower in patients with persistent preformed DSA and/or dnDSA. Each case of preformed DSA and dnDSA was associated with long-term graft survival. CONCLUSION The presence of persistent preformed DSA or dnDSA at 1 year posttransplantation may be a predictor of long-term graft survival. Further study is needed to evaluate whether periodic screening for DSA improves long-term graft survival.
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Affiliation(s)
- Nobuhiro Fujiyama
- Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Shigeru Satoh
- Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.
| | - Mitsuru Saito
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Kazuyuki Numakura
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Takamitsu Inoue
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Ryuhei Yamamoto
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Takuro Saito
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Sohei Kanda
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Shintaro Narita
- Department of Urology, Akita University School of Medicine, Akita, Japan
| | - Yoko Mitobe
- Center for Kidney Disease and Transplantation, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Tomonori Habuchi
- Department of Urology, Akita University School of Medicine, Akita, Japan
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