|
1
|
Abbas K, Mubarak M. Expanding role of antibodies in kidney transplantation. World J Transplant 2025; 15:99220. [DOI: 10.5500/wjt.v15.i1.99220] [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: 07/17/2024] [Revised: 10/21/2024] [Accepted: 11/07/2024] [Indexed: 11/26/2024] Open
Abstract
The role of antibodies in kidney transplant (KT) has evolved significantly over the past few decades. This role of antibodies in KT is multifaceted, encompassing both the challenges they pose in terms of antibody-mediated rejection (AMR) and the opportunities for improving transplant outcomes through better detection, prevention, and treatment strategies. As our understanding of the immunological mechanisms continues to evolve, so too will the approaches to managing and harnessing the power of antibodies in KT, ultimately leading to improved patient and graft survival. This narrative review explores the multifaceted roles of antibodies in KT, including their involvement in rejection mechanisms, advancements in desensitization protocols, AMR treatments, and their potential role in monitoring and improving graft survival.
Collapse
Affiliation(s)
- Khawar Abbas
- Department of Transplant Immunology, Sindh Institute of Urology & Transplantation, Karachi 74200, Sindh, Pakistan
| | - Muhammed Mubarak
- Javed I. Kazi Department of Histopathology, Sindh Institute of Urology & Transplantation, Karachi 74200, Sindh, Pakistan
| |
Collapse
|
|
2
|
Zanoni F, Obayemi JE, Gandla D, Castellano G, Keating BJ. Emerging role of genetics in kidney transplantation. Kidney Int 2025; 107:424-433. [PMID: 39710162 DOI: 10.1016/j.kint.2024.09.026] [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: 02/29/2024] [Revised: 09/16/2024] [Accepted: 09/25/2024] [Indexed: 12/24/2024]
Abstract
The advent of more affordable genomic analytical pipelines has facilitated the expansion of genetic studies in kidney transplantation. Advances in genetic sequencing have allowed for a greater understanding of the genetic basis of chronic kidney disease, which has helped to guide transplant management and address issues related to living donation in specific disease settings. Recent efforts have shown significant effects of genetic ancestry and donor APOL1 risk genotypes in determining worse allograft outcomes and increased donation risks. Genetic studies in kidney transplantation outcomes have started to assess the effects of donor and recipient genetics in primary disease recurrence and transplant-related comorbidities, while genome-wide donor-recipient genetic incompatibilities have been shown to represent an important determinant of alloimmunity. Future large-scale comprehensive studies will shed light on the clinical utility of integrative genomics in the kidney transplantation setting.
Collapse
Affiliation(s)
- Francesca Zanoni
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Transplantation, Department of Surgery, New York University Langone Health, Grossman School of Medicine, New York, New York, USA
| | - Joy E Obayemi
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA; Comprehensive Transplant Center, Department of Surgery, Northwestern University, Chicago Illinois, USA
| | - Divya Gandla
- Division of Transplantation, Department of Surgery, New York University Langone Health, Grossman School of Medicine, New York, New York, USA
| | - Giuseppe Castellano
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Science and Community Health, University of Milan, Milan, Italy
| | - Brendan J Keating
- Institute of Systems Genetics, New York University Langone Health, Grossman School of Medicine, New York, New York, USA.
| |
Collapse
|
|
3
|
Mahler CF, Friedl F, Nusshag C, Speer C, Benning L, Göth D, Schaier M, Sommerer C, Mieth M, Mehrabi A, Michalski C, Renders L, Bachmann Q, Heemann U, Krautter M, Schwenger V, Echterdiek F, Zeier M, Morath C, Kälble F. Evaluation of deceased-donor kidney offers: development and validation of novel data driven and expert based prediction models for early transplant outcomes. Front Immunol 2025; 15:1511368. [PMID: 39840033 PMCID: PMC11747414 DOI: 10.3389/fimmu.2024.1511368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 12/06/2024] [Indexed: 01/23/2025] Open
Abstract
In the face of growing transplant waitlists and aging donors, sound pre-transplant evaluation of organ offers is paramount. However, many transplant centres lack clear criteria on organ acceptance. Often, previous scores for donor characterisation have not been validated for the Eurotransplant population and are not established to support graft acceptance decisions. Here, we investigated 1353 kidney transplantations at three different German centres to develop and validate novel statistical models for the prediction of early adverse graft outcome (EAO), defined as graft loss or CKD ≥4 within three months. The predictive models use generalised estimating equations (GEE) accounting for potential correlations between paired grafts from the same donor. Discriminative accuracy and calibration were determined via internal and external validation in the development (935 recipients, 309 events) and validation cohort (418 recipients, 162 events) respectively. The expert model is based on predictor ratings by senior transplant nephrologists, while for the data-driven model variables were selected via high-dimensional lasso generalised estimating equations (LassoGee). Both models show moderate discrimination for EAO (C-statistic expert model: 0,699, data-driven model 0,698) with good calibration. In summary, we developed novel statistical models that represent current clinical consensus and are tailored to the older deceased donor population. Compared to KDRI, our described models are sparse with only four and three predictors respectively and account for paired grafts from the same donor, while maintaining a discriminative accuracy equal or better than the established KDRI-score.
Collapse
Affiliation(s)
- Christoph F. Mahler
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Felix Friedl
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Nusshag
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Claudius Speer
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Louise Benning
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Daniel Göth
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Matthias Schaier
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Claudia Sommerer
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Markus Mieth
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Christoph Michalski
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Lutz Renders
- Department of Nephrology, Klinikum Rechts der Isar, Technische Universität München (TUM), Munich, Germany
| | - Quirin Bachmann
- Department of Nephrology, Klinikum Rechts der Isar, Technische Universität München (TUM), Munich, Germany
| | - Uwe Heemann
- Department of Nephrology, Klinikum Rechts der Isar, Technische Universität München (TUM), Munich, Germany
| | - Markus Krautter
- Department of Nephrology, Hospital Stuttgart, Stuttgart, Germany
| | - Vedat Schwenger
- Department of Nephrology, Hospital Stuttgart, Stuttgart, Germany
| | - Fabian Echterdiek
- Department of Nephrology, Klinikum Rechts der Isar, Technische Universität München (TUM), Munich, Germany
- Department of Nephrology, Hospital Stuttgart, Stuttgart, Germany
| | - Martin Zeier
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Morath
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Florian Kälble
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| |
Collapse
|
|
4
|
Hansen SM, Koefoed-Nielsen P, Clemmensen TS, Eiskjær H, Staunstrup NH. Genomic collision at the LIMS-1 locus increases risk of cellular mediated allograft rejection in heart transplanted recipients. Hum Immunol 2025; 86:111189. [PMID: 39642779 DOI: 10.1016/j.humimm.2024.111189] [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: 06/02/2024] [Revised: 10/17/2024] [Accepted: 11/22/2024] [Indexed: 12/09/2024]
Abstract
Genomic collision at the LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1) locus between donor and heart recipient was examined for the association with diagnosis of acute cellular or antibody-mediated allograft rejection, ACR or ABMR, respectively. In this single center retrospective study, 129 heart transplanted patients and donors were genotyped for the LIMS1 rs893403 variant, where the G-allele is in almost complete linkage disequilibrium with a loss of function deletion. A total of 14 cases with genomic collision (recipient genotype GG and donor genotype AA/AG) were identified. After a median follow-up time of 723 days, the multivariate adjusted hazard ratio for ACR of 1.64 (95 % CI 0.66-4.1) indicated that genomic collision indeed was a risk factor, while the risk of ABMR was less affected by genotype. Although statistically not significant, due to low power, this study indicates that LIMS1 is a minor histocompatibility antigen in heart transplantation, associated with allograft rejection.
Collapse
Affiliation(s)
- Sandra Maria Hansen
- Department of Clinical Immunology, Aarhus University Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | | | - Hans Eiskjær
- Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
| | - Nicklas Heine Staunstrup
- Department of Clinical Immunology, Aarhus University Hospital, Denmark; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
| |
Collapse
|
|
5
|
Nieuwenhuis LM, Li Y, Loza BL, Lambeck AJ, Hu S, Gacesa R, Voskuil MD, Hepkema BG, Jansen BH, Blokzijl H, Verkade HJ, van den Heuvel MC, Asrani S, Testa G, Klintmalm G, Trotter J, Olthoff KM, Shaked A, Keating BJ, Weersma RK, Festen EA, de Meijer VE. Genome-wide meta-analysis associates donor-recipient non-HLA genetic mismatch with acute cellular rejection post-liver transplantation. Hepatol Commun 2025; 9:e0601. [PMID: 39670865 PMCID: PMC11637756 DOI: 10.1097/hc9.0000000000000601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/26/2024] [Indexed: 12/14/2024] Open
Abstract
BACKGROUND Acute cellular rejection (ACR) remains a common complication causing significant morbidity post-liver transplantation. Non-human leukocyte antigen (non-HLA) mismatches were associated with an increased risk of ACR in kidney transplantation. Therefore, we hypothesized that donor-recipient non-HLA genetic mismatch is associated with increased ACR incidence post-liver transplantation. METHODS We conducted an international multicenter case-control genome-wide association study of donor-recipient liver transplant pairs in 3 independent cohorts, totaling 1846 pairs. To assess genetic mismatch burden, we calculated sum scores for single-nucleotide polymorphism (SNP) mismatch based on all non-HLA functional SNPs, specifically SNPs coding for transmembrane or secreted proteins as they more likely affect the immune system. We analyzed the association between the non-HLA mismatch scores and ACR in a multivariable Cox regression model per cohort, followed by a weighted meta-analysis. RESULTS During the first year post-transplantation, 90 of 689 (13%), 161 of 720 (22%), and 48 of 437 (11%) recipients experienced ACR in cohorts 1-3, respectively. Weighted meta-analyses showed that higher mismatch in functional non-HLA SNPs was associated with an increased incidence of ACR (HR 5.99; 95% CI: 1.39-20.08; p=0.011). Moreover, we found a larger effect of mismatch in SNPs coding for transmembrane or secreted proteins on ACR (HR 7.54; 95% CI 1.95-28.79; p=0.003). Sensitivity analyses showed that imputed HLA mismatch did not affect the associations between both non-HLA mismatch scores and ACR. CONCLUSIONS Donor-recipient mismatch of functional non-HLA SNPs overall and, especially, of SNPs encoding transmembrane or secreted proteins correlated with 1-year ACR post-liver transplantation. Identifying high-risk immunological burdens between pairs may prevent early graft rejection and aid in personalizing immunosuppressive therapy. Future studies are, however, needed to validate our findings using a genotyped HLA cohort.
Collapse
Affiliation(s)
- Lianne M. Nieuwenhuis
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Yanni Li
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bao-Li Loza
- Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Annechien J.A. Lambeck
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Shixian Hu
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ranko Gacesa
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Michiel D. Voskuil
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bouke G. Hepkema
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bernadien H. Jansen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Henk-Jan Verkade
- Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands
| | - Marius C. van den Heuvel
- Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Sumeet Asrani
- Baylor University Medical Center, Dallas, Texas, USA
| | | | | | - James Trotter
- Baylor University Medical Center, Dallas, Texas, USA
| | - Kim M. Olthoff
- Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Abraham Shaked
- Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Brendan J. Keating
- Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eleonora A.M. Festen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
6
|
Yan H, Lan G, Peng Q, Zhang W, Wang Y, Li X. Causal associations between gut Bifidobacteriaceae and transplant failure: a Mendelian randomization study. Future Microbiol 2025; 20:23-31. [PMID: 39552557 DOI: 10.1080/17460913.2024.2417608] [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: 11/27/2023] [Accepted: 10/14/2024] [Indexed: 11/19/2024] Open
Abstract
Aim: Transplant rejection and failure are the primary causes of shortened lifespan in transplant patients and are closely associated with the status of the human immune system. Gut microbiota have the capacity to modulate the human immune system. However, it remains unclear whether any gut microbiota can influence the risk of transplant failure.Materials & methods: A Mendelian randomization study was conducted to explore the causal relationship between gut microbiota and transplant failure. This study utilized three Genome-Wide Association Study results focusing on the gut microbiome, transplant failure and transplantation status. Single nucleotide polymorphisms that were strongly associated with gut microbiota abundance were selected as instrumental variables.Results: The abundance of Bifidobacteriaceae demonstrated a significant causal relationship with transplant failure (inverse variance weighted [IVW] p = 0.049, OR = 0.658, 95% CI: 0.433-0.998), but was not related to the risk of transplantation status (IVW p > 0.200). Notably, a higher intestinal abundance of Bifidobacteriaceae corresponded to a decreased risk of transplant failure. Bifidobacteriaceae instrumental variables were enriched in pathways related to synapses and membranes.Conclusion: The Bifidobacteriaceae may play a crucial role in the mechanism of transplant failure. These study results contribute to elucidating the mechanisms underlying transplant failure.
Collapse
Affiliation(s)
- Han Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P.R. China
| | - Gongbin Lan
- Department of Kidney Transplantation, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P.R. China
| | - Qi Peng
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, P.R. China 410008
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, 410008, P.R. China
- National Clinical Research Center for Geriatric Disorders, Hunan, 410028, P.R. China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, P.R. China 410008
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, 410008, P.R. China
- National Clinical Research Center for Geriatric Disorders, Hunan, 410028, P.R. China
| | - Ying Wang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P.R. China
| | - Xi Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan, P.R. China 410008
- Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, 410008, P.R. China
- National Clinical Research Center for Geriatric Disorders, Hunan, 410028, P.R. China
| |
Collapse
|
|
7
|
Helanterä I, Markkinen S, Partanen J, Hyvärinen K. Novel Aspects of Immunogenetics and Post-Transplant Events in Kidney Transplantation. Transpl Int 2024; 37:13317. [PMID: 39703873 PMCID: PMC11655191 DOI: 10.3389/ti.2024.13317] [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: 05/30/2024] [Accepted: 11/25/2024] [Indexed: 12/21/2024]
Abstract
HLA typing and matching have been crucial in kidney transplantation, but methods for assessing tissue histocompatibility have advanced significantly. While serological-level HLA typing remains common, it captures only a small fraction of true HLA variation, and molecular matching is already replacing traditional HLA matching. Recent studies have expanded our understanding of genetic tissue compatibility beyond HLA loci. Candidate gene analyses and genome-wide association studies (GWAS) have identified genetic factors linked to post-transplant complications, though replication of these findings is challenging. An alternative approach involves genome-wide matching of genes or genetic variations. This method has shown promise in hematopoietic stem cell and kidney transplantation. For instance, homozygous gene deletions in LIMS1 or complement factor H (CFH) genes have been associated with acute rejection risk. This may be due to alloimmune responses against proteins absent in the patient but present in the graft, or due to the missing protein's function. Genetic studies in clinical medicine face challenges due to the interplay of genetic and environmental factors, necessitating large datasets for meaningful associations. International collaboration and large consortia, like iGeneTRAin, are essential for validating findings and advancing the field. This review highlights recent advancements in immunogenetics and tissue histocompatibility, emphasizing future research directions.
Collapse
Affiliation(s)
- Ilkka Helanterä
- Transplantation and Liver Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | | | | | | |
Collapse
|
|
8
|
Cucchiari D, Podestà MA, Ponticelli C. Pathophysiology of rejection in kidney transplantation. Expert Rev Clin Immunol 2024; 20:1471-1481. [PMID: 39467249 DOI: 10.1080/1744666x.2024.2421310] [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: 02/04/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024]
Abstract
INTRODUCTION Rejection remains a major obstacle to successful kidney transplantation. The complex pathophysiology of rejection depends on a fine-tuned interplay between the innate and adaptive immune systems. AREAS COVERED This review provides a comprehensive analysis of the pathophysiology of rejection of kidney grafts, performed through careful selection of most relevant papers available on the topic in the PubMed database. The two types of rejection usually observed at the kidney biopsy, i.e. cellular and humoral rejection, are described with an accurate outline of the biological processes that lead to their development. EXPERT OPINION The incidence of T-cell-mediated rejection is decreasing, and most cases promptly respond to appropriate immunosuppression. However, late diagnosis or incomplete response to treatment may have deleterious consequences in the long term. The main issue is represented by antibody-mediated rejection, which unsatisfactorily responds to aggressive immunosuppression, especially when diagnosed late. Prevention of acute ABMR rests on HLA-specific antibody detection prior to transplantation, adequate immunosuppression, and optimal patients' compliance. Late diagnosis and poor response to treatment inevitably lead to chronic ABMR, for which no therapies are currently available.
Collapse
Affiliation(s)
- David Cucchiari
- Department of Nephrology and Kidney Transplantation, Hospital Clínic, Barcelona, Spain
| | - Manuel Alfredo Podestà
- Transplantation Research Center, Renal Division, Brigham and Women's Hopsital, Harvard Medical School, Boston, MA, USA
| | | |
Collapse
|
|
9
|
Mujić Franić A, Lilić M, Katalinić N, Glavaš-Obrovac L. Comprehensive Characterization of Anti-HLA and Non-HLA Antibodies in Patients on Kidney Transplant Waiting List and Evaluation of Their Impact on Alloimmunization Risk and Dialysis Treatment. Int J Mol Sci 2024; 25:12103. [PMID: 39596170 PMCID: PMC11593988 DOI: 10.3390/ijms252212103] [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: 10/06/2024] [Revised: 11/02/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Alloimmunization remains a major obstacle to successful kidney transplantation, mainly due to the formation of anti-HLA antibodies. In recent years, non-HLA antibodies have emerged as additional immunologic factors that can potentially contribute to graft rejection. The aim of this study was to investigate the prevalence and specificity of both anti-HLA and non-HLA antibodies in patients with end-stage renal disease on a waiting list for kidney transplantation. Serum samples from 74 patients were analyzed using complement-dependent cytotoxicity and solid-phase assays. IgG anti-HLA antibodies were identified in 43.2% of participants, while IgG non-HLA antibodies were detected in 91.9%. The most frequent non-HLA antibodies included anti-ENO1 (28.4%), anti-FIBR1 (23.0%) and anti-PRKCZ (23.0%). A significant difference was found between the number of distinct IgG anti-HLA and IgG non-HLA antibody specificities. However, no significant correlation was found between the number of IgG non-HLA antibody specificities and previous alloimmunization events or dialysis treatments. These results suggest that non-HLA antibodies, although often overlooked, can sometimes play a critical role in transplant outcomes. Routine testing for non-HLA antibodies, in addition to mandatory anti-HLA antibody screening and identification, could improve immunologic risk assessment in transplant patients and post-transplant care.
Collapse
Affiliation(s)
- Aida Mujić Franić
- Laboratory for Tissue Typing, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (A.M.F.); (N.K.)
| | - Marko Lilić
- School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Nataša Katalinić
- Laboratory for Tissue Typing, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia; (A.M.F.); (N.K.)
- Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
| | - Ljubica Glavaš-Obrovac
- Department of Medicinal Chemistry, Biochemistry and Clinical Chemistry, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| |
Collapse
|
|
10
|
Feng Y, Xu S, Feng Y, Zhao N, Xu L, Fang Y, Xu H, Mao L, Wang Z, Guo J, Feng G, Rao J, Shang W. Genetic testing in pediatric kidney transplant recipients to promote informed choice and improve individualized monitoring. Orphanet J Rare Dis 2024; 19:366. [PMID: 39363361 PMCID: PMC11448020 DOI: 10.1186/s13023-024-03379-4] [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: 06/29/2024] [Accepted: 09/22/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND The growing body of research on kidney disease in children has identified a broad spectrum of genetic etiologies. METHODS We conducted a prospective study to evaluate the efficacy of an optimized genetic test and subclinical changes in a real-world context before kidney transplantation. All cases involved recipients under the age of 18 who underwent whole exome sequencing (ES) between 2013 and 2022. RESULTS The study population included 244 children, with a median age of 13.1 years at transplantation. ES provided a molecular genetic diagnosis in 114 (46.7%) probands with monogenic variants in 15 known disease-causing genes. ES confirmed the suspected clinical diagnosis in 74/244 (30.3%) cases and revised the pre-exome clinical diagnoses in 40/244 (16.4%) cases. ES also established a specific underlying cause for kidney failure for 19 patients who had previously had an unknown etiology. Genetic diagnosis influenced clinical management in 88 recipients (36.1%), facilitated genetic counseling for 18 families (7.4%), and enabled comprehensive assessment of living donor candidates in 35 cases (14.3%). CONCLUSIONS Genetic diagnosis provides critical insights into the pathogenesis of kidney disease, optimizes clinical strategies concerning risk assessment of living donors, and enhances disease surveillance of recipients.
Collapse
Affiliation(s)
- Yonghua Feng
- Department of Renal Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Shicheng Xu
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Daxuebei Road No. 40, Zhengzhou, 450052, China
- Academy of Medical Sciences, Precision Medicine Center of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Yi Feng
- Department of Renal Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Na Zhao
- Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, No. 399 Wanyuan Road, Shanghai, 201102, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Linan Xu
- Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, No. 399 Wanyuan Road, Shanghai, 201102, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Ye Fang
- Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, No. 399 Wanyuan Road, Shanghai, 201102, China
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Hongen Xu
- Academy of Medical Sciences, Precision Medicine Center of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Lu Mao
- Academy of Medical Sciences, Precision Medicine Center of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Zhigang Wang
- Department of Renal Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China
| | - Jiancheng Guo
- The Research and Application Center of Precision Medicine, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China
| | - Guiwen Feng
- Department of Renal Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
| | - Jia Rao
- Department of Nephrology, Children's Hospital of Fudan University, National Pediatric Medical Center of CHINA, No. 399 Wanyuan Road, Shanghai, 201102, China.
- Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China.
- National Key Laboratory of Kidney Diseases, Beijing, 100853, China.
| | - Wenjun Shang
- Department of Renal Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
| |
Collapse
|
|
11
|
Mattoo A, Jaffe IS, Keating B, Montgomery RA, Mangiola M. Improving long-term kidney allograft survival by rethinking HLA compatibility: from molecular matching to non-HLA genes. Front Genet 2024; 15:1442018. [PMID: 39415982 PMCID: PMC11480002 DOI: 10.3389/fgene.2024.1442018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 09/19/2024] [Indexed: 10/19/2024] Open
Abstract
Optimizing immunologic compatibility in organ transplantation extends beyond the conventional approach of Human Leukocyte Antigen (HLA) antigen matching, which exhibits significant limitations. A broader comprehension of the roles of classical and non-classical HLA genes in transplantation is imperative for enhancing long-term graft survival. High-resolution molecular HLA genotyping, despite its inherent challenges, has emerged as the cornerstone for precise patient-donor compatibility assessment. Leveraging understanding of eplet biology and indirect immune activation, eplet mismatch calculators and the PIRCHE-II algorithm surpass traditional methods in predicting allograft rejection. Understanding minor histocompatibility antigens may also present an opportunity to personalize the compatibility process. While the application of molecular matching in deceased donor organ allocation presents multiple technical, logistical, and conceptual barriers, rendering it premature for mainstream use, several other areas of donor-recipient matching and post-transplant management are ready to incorporate molecular matching. Provision of molecular mismatch scores to physicians during potential organ offer evaluations could potentially amplify long-term outcomes. The implementation of molecular matching in living organ donation and kidney paired exchange programs is similarly viable. This article will explore the current understanding of immunologic matching in transplantation and the potential applications of epitope and non-epitope molecular biology and genetics in clinical transplantation.
Collapse
Affiliation(s)
- Aprajita Mattoo
- *Correspondence: Aprajita Mattoo, ; Ian S. Jaffe, ; Massimo Mangiola,
| | - Ian S. Jaffe
- *Correspondence: Aprajita Mattoo, ; Ian S. Jaffe, ; Massimo Mangiola,
| | | | | | - Massimo Mangiola
- NYU Langone Transplant Institute, New York University Langone Health, New York, NY, United States
| |
Collapse
|
|
12
|
Alhamdan F, Coppolino A, Sheikh A, Miele A, Lee S, Gasiewski A, Brescia P, Wood I, Venkat A, Thaniyavarn T, Jacob S, Keshk M, Meadowcroft S, Banday MM, Khan MM, Hayes D, Chandrekar A, Goldberg H, Guleria I, Sharma NS. Distinct Non-Human Leukocyte Antigen Antibody Signatures Correlate with Endothelial Crossmatch Status in Lung and Renal Transplant Recipients. Int J Mol Sci 2024; 25:10562. [PMID: 39408890 PMCID: PMC11476851 DOI: 10.3390/ijms251910562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/20/2024] Open
Abstract
Non-HLA antibodies against heterogeneous targets on endothelial cells have been associated with allograft injuries. The endothelial cell crossmatch (ECXM) is used in the detection of non-HLA antibodies but remains non-discriminatory for specific antibody identification. The primary objective of this study was to delineate the specific non-HLA antibody signatures associated with ECXM positivity and to determine the correlation of ECXM status and non-HLA antibody signatures on allograft health. Serum specimens from 25 lung transplant recipients (LTRs) and 13 renal transplant recipients (RTRs) were collected as part of clinical evaluation, and testing for angiotensin II receptor type 1 (AT1R) and donor-specific MHC class I chain-related gene A (MICA) antibodies and ECXM was performed. Remnant sera were tested for non-HLA antibodies using the LABScreen™ Autoantibody (LSAUT) Group 1, 2, and 3 kits (One Lambda, Inc., Los Angeles, CA, USA). In both cohorts, the concordance of AT1R and MICA together or individually with ECXM+ status was poor (<0.7), suggesting the presence of other unaccounted antibodies. Autoantibody profiling revealed three distinct clusters targeting fibrotic products, cytoskeletal proteins, and cell signaling molecules. A comparative analysis of ECXM+ and ECXM- specimens identified nine and five differentially expressed antibodies in the LTR and RTR cohorts, respectively. Employing machine learning techniques (variable importance, feature selection, ROC-AUC), we derived a five-antibody panel (TNFα, collagen V, CXCL11, GDNF, GAPDH) and a two-antibody panel (TNFα, CXCL9) that effectively discriminated between ECXM+ and ECXM- status in the LTR and RTR cohorts, respectively. Distinct antibody signatures were identified in LTR and RTR cohorts that correlated with ECXM+ status and were associated with allograft dysfunction.
Collapse
Affiliation(s)
- Fahd Alhamdan
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Antonio Coppolino
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Adil Sheikh
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Anna Miele
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Stefi Lee
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
- VA Boston Medical Center, Boston, MA 02130, USA
| | - Allison Gasiewski
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Peter Brescia
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Isabelle Wood
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Arvin Venkat
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Tany Thaniyavarn
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
- VA Boston Medical Center, Boston, MA 02130, USA
| | - Selvin Jacob
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Mohamed Keshk
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Stacia Meadowcroft
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Mudassir M. Banday
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Mohd Moin Khan
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Don Hayes
- Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA;
| | - Anil Chandrekar
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Hilary Goldberg
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Indira Guleria
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
| | - Nirmal S. Sharma
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; (F.A.); (A.C.); (A.S.); (A.M.); (S.L.); (A.G.); (P.B.); (I.W.); (A.V.); (T.T.); (S.J.); (M.K.); (S.M.); (M.M.B.); (M.M.K.); (A.C.); (H.G.); (I.G.)
- VA Boston Medical Center, Boston, MA 02130, USA
| |
Collapse
|
|
13
|
Ni WJ, Li ZL, Wen XL, Ji JL, Liu H, Yin Q, Jiang LYZ, Zhang YL, Wen Y, Tang TT, Jiang W, Lv LL, Gan WH, Liu BC, Wang B. HIF-1α and adaptor protein LIM and senescent cell antigen-like domains protein 1 axis promotes tubulointerstitial fibrosis by interacting with vimentin in angiotensin II-induced hypertension. Br J Pharmacol 2024; 181:3098-3117. [PMID: 38698737 DOI: 10.1111/bph.16358] [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: 09/22/2023] [Revised: 01/03/2024] [Accepted: 02/05/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND AND PURPOSE Activation of the renin-angiotensin system, as a hallmark of hypertension and chronic kidney diseases (CKD) is the key pathophysiological factor contributing to the progression of tubulointerstitial fibrosis. LIM and senescent cell antigen-like domains protein 1 (LIMS1) plays an essential role in controlling of cell behaviour through the formation of complexes with other proteins. Here, the function and regulation of LIMS1 in angiotensin II (Ang II)-induced hypertension and tubulointerstitial fibrosis was investigated. EXPERIMENTAL APPROACH C57BL/6 mice were treated with Ang II to induce tubulointerstitial fibrosis. Hypoxia-inducible factor-1α (HIF-1α) renal tubular-specific knockout mice or LIMS1 knockdown AAV was used to investigate their effects on Ang II-induced renal interstitial fibrosis. In vitro, HIF-1α or LIMS1 was knocked down or overexpressed in HK2 cells after exposure to Ang II. KEY RESULTS Increased expression of tubular LIMS1 was observed in human kidney with hypertensive nephropathy and in murine kidney from Ang II-induced hypertension model. Tubular-specific knockdown of LIMS1 ameliorated Ang II-induced tubulointerstitial fibrosis in mice. Furthermore, we demonstrated that LIMS1 was transcriptionally regulated by HIF-1α in tubular cells and that tubular HIF-1α knockout ameliorates LIMS1-mediated tubulointerstitial fibrosis. In addition, LIMS1 promotes Ang II-induced tubulointerstitial fibrosis by interacting with vimentin. CONCLUSION AND IMPLICATIONS We conclude that HIF-1α transcriptionally regulated LIMS1 plays a central role in Ang II-induced tubulointerstitial fibrosis through interacting with vimentin. Our finding represents a new insight into the mechanism of Ang II-induced tubulointerstitial fibrosis and provides a novel therapeutic target for progression of CKD.
Collapse
Affiliation(s)
- Wei-Jie Ni
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Zuo-Lin Li
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Xian-Li Wen
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jia-Ling Ji
- Department of Pediatrics, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hong Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Qing Yin
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Liang-Yun-Zi Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yi-Lin Zhang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yi Wen
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Tao-Tao Tang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Wei Jiang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Lin-Li Lv
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Wei-Hua Gan
- Department of Pediatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Bin Wang
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| |
Collapse
|
|
14
|
Caliskan Y, Ozluk Y, Kurashima K, Mirioglu S, Dirim AB, Hurdogan O, Oto OA, Syn M, Nazzal M, Jain A, Edwards J, Yazici H, Lentine KL. LIM Zinc Finger Domain Containing 1 Risk Genotype of Recipient Is Associated with Renal Tubular Inflammation in Kidney Transplantation. Genes (Basel) 2024; 15:773. [PMID: 38927709 PMCID: PMC11203101 DOI: 10.3390/genes15060773] [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: 05/07/2024] [Revised: 06/06/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Homozygosity for LIMS1 rs893403-GG genotype is linked to an increased risk of allograft rejection after kidney transplantation. Ischemia-reperfusion of the kidney allograft leads to long term infiltration of activated and effector-memory T lymphocytes and resulting in rejection and long-term fibrosis. However, the genotype, LIMS1 expression under ischemic conditions and the long-term histopathological relationships remain ill-defined. METHODS We examined the impact of the recipient's LIMS1-rs893403 genotype with transplant kidney histopathology. The association of the LIMS1-rs893403 genotype and LIMS1 and GCC2 mRNA expression in ischemic donor kidneys were also examined. Recipients who underwent transplant kidney biopsy were genotyped for the LIMS1-rs893403 variant and associated deletion. Histopathological findings were compared between recipients with LIMS1 risk and non-risk genotypes. Real-time PCR and immunofluorescence staining for LIMS1 and GCC2 expression were performed in non-utilized donor kidneys. RESULTS Demographic, clinical, and treatment characteristics and the histopathological diagnosis were similar between recipients with rs893403 GG and AA/AG genotype. The Banff tubulitis score was higher in GG recipients (n = 24) compared to AA/AG (n = 86) recipients (1.42 ± 0.65 vs. 1.12 ± 0.66, p = 0.03). Ischemic kidneys with GG showed higher LIMS1 and GCC2 mRNA expression than kidneys with AG. Kidneys with rs893403-GG had higher tubular LIMS1 and GCC2 immunohistochemical staining compared to kidneys with rs893403-AG. CONCLUSIONS Our data supports the role of the LIMS1 locus in kidney transplant rejection, particularly in lymphocyte infiltration into the internal aspect of the tubular basement membranes. Increased LIMS1 and GCC2 expression in ischemic donor kidneys with the GG genotype require further studies.
Collapse
Affiliation(s)
- Yasar Caliskan
- Division of Nephrology, SSM Saint Louis University Hospital, Saint Louis, MO 63110, USA; (J.E.); (K.L.L.)
- Division of Nephrology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (S.M.); (A.B.D.); (O.A.O.); (H.Y.)
| | - Yasemin Ozluk
- Department of Pathology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (Y.O.); (O.H.)
| | - Kento Kurashima
- Department of Pediatrics, School of Medicine, SSM Saint Louis University, Saint Louis, MO 63104, USA; (K.K.); (M.S.); (A.J.)
| | - Safak Mirioglu
- Division of Nephrology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (S.M.); (A.B.D.); (O.A.O.); (H.Y.)
| | - Ahmet Burak Dirim
- Division of Nephrology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (S.M.); (A.B.D.); (O.A.O.); (H.Y.)
| | - Ozge Hurdogan
- Department of Pathology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (Y.O.); (O.H.)
| | - Ozgur Akin Oto
- Division of Nephrology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (S.M.); (A.B.D.); (O.A.O.); (H.Y.)
| | - Marzena Syn
- Department of Pediatrics, School of Medicine, SSM Saint Louis University, Saint Louis, MO 63104, USA; (K.K.); (M.S.); (A.J.)
| | - Mustafa Nazzal
- Department of Surgery, SSM Saint Louis University Hospital, Saint Louis, MO 63110, USA;
| | - Ajay Jain
- Department of Pediatrics, School of Medicine, SSM Saint Louis University, Saint Louis, MO 63104, USA; (K.K.); (M.S.); (A.J.)
| | - John Edwards
- Division of Nephrology, SSM Saint Louis University Hospital, Saint Louis, MO 63110, USA; (J.E.); (K.L.L.)
| | - Halil Yazici
- Division of Nephrology, Istanbul School of Medicine, Istanbul University, Istanbul 34093, Turkey; (S.M.); (A.B.D.); (O.A.O.); (H.Y.)
| | - Krista L. Lentine
- Division of Nephrology, SSM Saint Louis University Hospital, Saint Louis, MO 63110, USA; (J.E.); (K.L.L.)
| |
Collapse
|
|
15
|
Qi J, Li H, Du Y, Liu Y, He W, Meng J, Wei L, Zhang K, Lu Y, Zhu X. Circulating Autoantibody Profiling Identifies LIMS1 as a Potential Target for Pathogenic Autoimmunity in pathologic Myopia. Mol Cell Proteomics 2024; 23:100783. [PMID: 38729610 PMCID: PMC11215957 DOI: 10.1016/j.mcpro.2024.100783] [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: 10/16/2023] [Revised: 04/22/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024] Open
Abstract
High myopia is a leading cause of blindness worldwide, among which pathologic myopia, characterized by typical myopic macular degeneration, is the most detrimental. However, its pathogenesis remains largely unknown. Here, using a HuProt array, we first initiated a serological autoantibody profiling of high myopia and identified 18 potential autoantibodies, of which anti-LIMS1 autoantibody was validated by a customized focused microarray. Further subgroup analysis revealed its actual relevance to pathologic myopia, rather than simple high myopia without myopic macular degeneration. Mechanistically, anti-LIMS1 autoantibody predominantly belonged to IgG1/IgG2/IgG3 subclasses. Serum IgG obtained from patients with pathologic myopia could disrupt the barrier function of retinal pigment epithelial cells via cytoskeleton disorganization and tight junction component reduction, and also trigger a pro-inflammatory mediator cascade in retinal pigment epithelial cells, which were all attenuated by depletion of anti-LIMS1 autoantibody. Together, these data uncover a previously unrecognized autoimmune etiology of myopic macular degeneration in pathologic myopia.
Collapse
Affiliation(s)
- Jiao Qi
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China
| | - Hao Li
- Department of Ophthalmology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
| | - Yu Du
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China
| | - Yun Liu
- MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Wenwen He
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China
| | - Jiaqi Meng
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China
| | - Ling Wei
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China
| | - Keke Zhang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China
| | - Yi Lu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China.
| | - Xiangjia Zhu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, People's Republic of China; NHC Key Laboratory of Myopia and Related Eye Diseases, Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, People's Republic of China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, People's Republic of China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People's Republic of China.
| |
Collapse
|
|
16
|
Zanoni F, Neugut YD, Obayemi JE, Liu L, Zhang JY, Ratner LE, Cohen DJ, Mohan S, Gharavi AG, Keating B, Kiryluk K. Genetic versus self-reported African ancestry of the recipient and neighborhood predictors of kidney transplantation outcomes in 2 multiethnic urban cohorts. Am J Transplant 2024; 24:1003-1015. [PMID: 38331047 PMCID: PMC11144562 DOI: 10.1016/j.ajt.2024.01.033] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 01/25/2024] [Accepted: 01/28/2024] [Indexed: 02/10/2024]
Abstract
African American (AA) kidney recipients have a higher risk of allograft rejection and failure compared to non-AAs, but to what extent these outcomes are due to genetic versus environmental effects is currently unknown. Herein, we tested the effects of recipient self-reported race versus genetic proportion of African ancestry (pAFR), and neighborhood socioeconomic status (SES) on kidney allograft outcomes in multiethnic kidney transplant recipients from Columbia University (N = 1083) and the University of Pennsylvania (N = 738). All participants were genotyped with SNP arrays to estimate genetic admixture proportions. US census tract variables were used to analyze the effect of neighborhood factors. In both cohorts, self-reported recipient AA race and pAFR were individually associated with increased risk of rejection and failure after adjustment for known clinical risk factors and neighborhood SES factors. Joint analysis confirmed that self-reported recipient AA race and pAFR were both associated with a higher risk of allograft rejection (AA: HR 1.61 (1.31-1.96), P = 4.05E-06; pAFR: HR 1.90 (1.46-2.48), P = 2.40E-06) and allograft failure (AA: HR 1.52 (1.18-1.97), P = .001; pAFR: HR 1.70 (1.22-2.35), P = .002). Further research is needed to disentangle the role of genetics versus environmental, social, and structural factors contributing to poor transplantation outcomes in kidney recipients of African ancestry.
Collapse
Affiliation(s)
- Francesca Zanoni
- Department of Nephrology, Dialysis and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA; Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Y Dana Neugut
- Division of Pediatric Gastroenterology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Joy E Obayemi
- Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | - Lili Liu
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Jun Y Zhang
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Lloyd E Ratner
- Department of Surgery, Columbia University, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - David J Cohen
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Sumit Mohan
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Ali G Gharavi
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Brendan Keating
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Krzysztof Kiryluk
- Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.
| |
Collapse
|
|
17
|
Cao R, Schladt DP, Dorr C, Matas AJ, Oetting WS, Jacobson PA, Israni A, Chen J, Guan W. Polygenic risk score for acute rejection based on donor-recipient non-HLA genotype mismatch. PLoS One 2024; 19:e0303446. [PMID: 38820342 PMCID: PMC11142483 DOI: 10.1371/journal.pone.0303446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 04/24/2024] [Indexed: 06/02/2024] Open
Abstract
BACKGROUND Acute rejection (AR) after kidney transplantation is an important allograft complication. To reduce the risk of post-transplant AR, determination of kidney transplant donor-recipient mismatching focuses on blood type and human leukocyte antigens (HLA), while it remains unclear whether non-HLA genetic mismatching is related to post-transplant complications. METHODS We carried out a genome-wide scan (HLA and non-HLA regions) on AR with a large kidney transplant cohort of 784 living donor-recipient pairs of European ancestry. An AR polygenic risk score (PRS) was constructed with the non-HLA single nucleotide polymorphisms (SNPs) filtered by independence (r2 < 0.2) and P-value (< 1×10-3) criteria. The PRS was validated in an independent cohort of 352 living donor-recipient pairs. RESULTS By the genome-wide scan, we identified one significant SNP rs6749137 with HR = 2.49 and P-value = 2.15×10-8. 1,307 non-HLA PRS SNPs passed the clumping plus thresholding and the PRS exhibited significant association with the AR in the validation cohort (HR = 1.54, 95% CI = (1.07, 2.22), p = 0.019). Further pathway analysis attributed the PRS genes into 13 categories, and the over-representation test identified 42 significant biological processes, the most significant of which is the cell morphogenesis (GO:0000902), with 4.08 fold of the percentage from homo species reference and FDR-adjusted P-value = 8.6×10-4. CONCLUSIONS Our results show the importance of donor-recipient mismatching in non-HLA regions. Additional work will be needed to understand the role of SNPs included in the PRS and to further improve donor-recipient genetic matching algorithms. Trial registry: Deterioration of Kidney Allograft Function Genomics (NCT00270712) and Genomics of Kidney Transplantation (NCT01714440) are registered on ClinicalTrials.gov.
Collapse
Affiliation(s)
- Rui Cao
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - David P. Schladt
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States of America
| | - Casey Dorr
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States of America
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Arthur J. Matas
- Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - William S. Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Pamala A. Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, United States of America
| | - Ajay Israni
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, United States of America
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Jinbo Chen
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Weihua Guan
- Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America
| |
Collapse
|
|
18
|
Fedrigo M, Berry GJ, Coutance G, Reed EF, Lin CY, Giarraputo A, Kransdorf E, Thaunat O, Goddard M, Angelini A, Neil DAH, Bruneval P, Duong Van Huyen JP, Loupy A, Miller DV. Report of the 2022 Banff Heart Concurrent: Focus on non-human leukocyte antigen antibodies in rejection and the pathology of "mixed" rejection. Am J Transplant 2024; 24:533-541. [PMID: 37838218 DOI: 10.1016/j.ajt.2023.10.004] [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: 09/02/2023] [Revised: 10/03/2023] [Accepted: 10/03/2023] [Indexed: 10/16/2023]
Abstract
The Banff Heart Concurrent Session, held as part of the 16th Banff Foundation for Allograft Pathology Conference at Banff, Alberta, Canada, on September 21, 2022, focused on 2 major topics: non-human leukocyte antigen (HLA) antibodies and mixed rejection. Each topic was addressed in a multidisciplinary fashion with clinical, immunological, and pathology perspectives and future developments and prospectives. Following the Banff organization model and principles, the collective aim of the speakers on each topic was to • Determine current knowledge gaps in heart transplant pathology • Identify limitations of current pathology classification systems • Discuss next steps in addressing gaps and refining classification system.
Collapse
Affiliation(s)
- Marny Fedrigo
- Department of Cardiac, Thoracic and Vascular Sciences, and Public Health, University of Padova, Padua Italy
| | - Gerald J Berry
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
| | - Guillaume Coutance
- Department of cardiac surgery, La Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (APHP), Sorbonne University Medical School, Paris France
| | - Elaine F Reed
- UCLA Immunogenetics Center, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Chieh-Yu Lin
- Department of Pathology and Immunology, School of Medicine, Washington University St. Louis, Missouri, USA
| | - Alessia Giarraputo
- Department of Cardiac, Thoracic and Vascular Sciences, and Public Health, University of Padova, Padua Italy
| | - Evan Kransdorf
- Smidt Heart Institute, Cedars-Sinai Medical Center, Beverly Hills, California, USA
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon France
| | - Martin Goddard
- The Cardiothoracic Transplant Unit Papworth Hospital, Cambridge, United Kingdom
| | - Annalisa Angelini
- Department of Cardiac, Thoracic and Vascular Sciences, and Public Health, University of Padova, Padua Italy
| | - Desley A H Neil
- University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Patrick Bruneval
- Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | | | - Alexandre Loupy
- Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Dylan V Miller
- Utah Transplant Affiliated Hospitals (UTAH) Heart Transplant Network, Intermountain Central Laboratory, Salt Lake City, Utah, USA.
| |
Collapse
|
|
19
|
Mirioglu S, Kiran B, Lentine KL, Edwards JC, Caliskan Y. Regulatory T cells in kidney transplant recipients with LIMS1 rs893403 risk genotype. Clin Transplant 2024; 38:e15293. [PMID: 38545889 PMCID: PMC10987072 DOI: 10.1111/ctr.15293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 04/04/2024]
Affiliation(s)
- Safak Mirioglu
- Division of Nephrology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
- Department of Immunology, Istanbul University Aziz Sancar Institute of Experimental Medicine, Istanbul, Turkey
| | - Bayram Kiran
- Department of Genetics and Bioengineering, Kastamonu University, Kastamonu, Turkey
| | - Krista L. Lentine
- Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - John C. Edwards
- Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, MO, USA
| | - Yasar Caliskan
- Division of Nephrology, Istanbul University Istanbul Faculty of Medicine, Istanbul, Turkey
- Division of Nephrology, Saint Louis University School of Medicine, Saint Louis, MO, USA
| |
Collapse
|
|
20
|
Pérez-Sáez MJ, Montero N, Oliveras L, Redondo-Pachón D, Martínez-Simón D, Abramovicz D, Maggiore U, Mariat C, Mjoen G, Oniscu GC, Peruzzi L, Sever MS, Watschinger B, Velioglu A, Demir E, Gandolfini I, Hellemans R, Hilbrands L, Pascual J, Crespo M. Immunosuppression of HLA identical living-donor kidney transplant recipients: A systematic review. Transplant Rev (Orlando) 2023; 37:100787. [PMID: 37657355 DOI: 10.1016/j.trre.2023.100787] [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: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 09/03/2023]
Abstract
BACKGROUND Kidney transplant (KT) recipients of HLA identical siblings (HLAid) have lower immunological risk, but there are no specific recommendations for immunosuppression. Our aim was to analyze evidence about results from HLAid living-donor recipients under different immunosuppression in the current era of immunological risk assessment. METHODS Systematic review of studies describing associations between outcomes of HLAid living-donor KT recipients according to their immunological risk and applied immunosuppression. RESULTS From 1351 studies, 16 (5636 KT recipients) were included in the analysis. All studies were retrospective, ten comparing immunosuppression strategies, and six immunological risk strata. Of those ten, six studies were published in 1990 or earlier and only three included tacrolimus. The evidence is poor, and the inclusion of calcineurin inhibitors does not demonstrate better results. Furthermore, only few studies describe different immunosuppression regimens according to the patient immunological risk and, in general, they do not include the assessment with new solid phase assays. CONCLUSIONS There are no studies analyzing the association of outcomes of HLAid KT recipients with current immunological risk tools. In the absence of evidence, no decision or proposal of immunosuppression adapted to modern immunological risk assessment can be made currently by the Descartes Working Group.
Collapse
Affiliation(s)
| | - Núria Montero
- Nephrology Department, Hospital de Bellvitge, Barcelona, Spain
| | - Laia Oliveras
- Nephrology Department, Hospital de Bellvitge, Barcelona, Spain
| | | | | | - Daniel Abramovicz
- Department of Nephrology, Antwerp University Hospital, Antwerp, Belgium
| | - Umberto Maggiore
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Christophe Mariat
- Nephrology Dialysis and Renal Transplantation Dpt, CHU de Saint-Etienne, Université Jean Monnet, Saint-Etienne, France
| | - Geir Mjoen
- Department of Transplant Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Children's Hospital, Turin, Italy
| | - Mehmet Sükrü Sever
- Division of Nephrology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Bruno Watschinger
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Arzu Velioglu
- Marmara University, School of Medicine, Department of Nephrology, Istanbul, Turkey
| | - Erol Demir
- Transplant Immunology Research Centre of Excellence, Koç University Hospital, Istanbul, Turkey
| | - Ilaria Gandolfini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Rachel Hellemans
- Department of Nephrology, Antwerp University Hospital, Antwerp, Belgium
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Julio Pascual
- Nephrology Department, Hospital del Mar, Barcelona, Spain
| | - Marta Crespo
- Nephrology Department, Hospital del Mar, Barcelona, Spain.
| |
Collapse
|
|
21
|
Ba R, Durand A, Mauduit V, Chauveau C, Le Bas-Bernardet S, Salle S, Guérif P, Morin M, Petit C, Douillard V, Rousseau O, Blancho G, Kerleau C, Vince N, Giral M, Gourraud PA, Limou S. KiT-GENIE, the French genetic biobank of kidney transplantation. Eur J Hum Genet 2023; 31:1291-1299. [PMID: 36737541 PMCID: PMC10620190 DOI: 10.1038/s41431-023-01294-z] [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: 10/04/2022] [Revised: 12/16/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
KiT-GENIE is a monocentric DNA biobank set up to consolidate the very rich and homogeneous DIVAT French cohort of kidney donors and recipients (D/R) in order to explore the molecular factors involved in kidney transplantation outcomes. We collected DNA samples for kidney transplantations performed in Nantes, and we leveraged GWAS genotyping data for securing high-quality genetic data with deep SNP and HLA annotations through imputations and for inferring D/R genetic ancestry. Overall, the biobank included 4217 individuals (n = 1945 D + 2,272 R, including 1969 D/R pairs), 7.4 M SNPs and over 200 clinical variables. KiT-GENIE represents an accurate snapshot of kidney transplantation clinical practice in Nantes between 2002 and 2018, with an enrichment in living kidney donors (17%) and recipients with focal segmental glomerulosclerosis (4%). Recipients were predominantly male (63%), of European ancestry (93%), with a mean age of 51yo and 86% experienced their first graft over the study period. D/R pairs were 93% from European ancestry, and 95% pairs exhibited at least one HLA allelic mismatch. The mean follow-up time was 6.7 years with a hindsight up to 25 years. Recipients experienced biopsy-proven rejection and graft loss for 16.6% and 21.3%, respectively. KiT-GENIE constitutes one of the largest kidney transplantation genetic cohorts worldwide to date. It includes homogeneous high-quality clinical and genetic data for donors and recipients, hence offering a unique opportunity to investigate immunogenetic and genetic factors, as well as donor-recipient interactions and mismatches involved in rejection, graft survival, primary disease recurrence and other comorbidities.
Collapse
Affiliation(s)
- Rokhaya Ba
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Axelle Durand
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Vincent Mauduit
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Christine Chauveau
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Sonia Salle
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Pierrick Guérif
- CHU Nantes, Nantes Université, Service de Néphrologie-Immunologie Clinique, ITUN, F-44000, Nantes, France
| | - Martin Morin
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Clémence Petit
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
- CHU Nantes, Nantes Université, Service de Néphrologie-Immunologie Clinique, ITUN, F-44000, Nantes, France
| | - Venceslas Douillard
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Olivia Rousseau
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Gilles Blancho
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
- CHU Nantes, Nantes Université, Service de Néphrologie-Immunologie Clinique, ITUN, F-44000, Nantes, France
| | - Clarisse Kerleau
- CHU Nantes, Nantes Université, Service de Néphrologie-Immunologie Clinique, ITUN, F-44000, Nantes, France
| | - Nicolas Vince
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Magali Giral
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
- CHU Nantes, Nantes Université, Service de Néphrologie-Immunologie Clinique, ITUN, F-44000, Nantes, France
| | - Pierre-Antoine Gourraud
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France
| | - Sophie Limou
- Nantes Université, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche Translationnelle en Transplantation et Immunologie, UMR 1064, F-44000, Nantes, France.
| |
Collapse
|
|
22
|
Sun Z, Zhang Z, Banu K, Gibson IW, Colvin RB, Yi Z, Zhang W, De Kumar B, Reghuvaran A, Pell J, Manes TD, Djamali A, Gallon L, O’Connell PJ, He JC, Pober JS, Heeger PS, Menon MC. Multiscale genetic architecture of donor-recipient differences reveals intronic LIMS1 mismatches associated with kidney transplant survival. J Clin Invest 2023; 133:e170420. [PMID: 37676733 PMCID: PMC10617779 DOI: 10.1172/jci170420] [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: 03/13/2023] [Accepted: 09/06/2023] [Indexed: 09/09/2023] Open
Abstract
Donor-recipient (D-R) mismatches outside of human leukocyte antigens (HLAs) contribute to kidney allograft loss, but the mechanisms remain unclear, specifically for intronic mismatches. We quantified non-HLA mismatches at variant-, gene-, and genome-wide scales from single nucleotide polymorphism (SNP) data of D-Rs from 2 well-phenotyped transplant cohorts: Genomics of Chronic Allograft Rejection (GoCAR; n = 385) and Clinical Trials in Organ Transplantation-01/17 (CTOT-01/17; n = 146). Unbiased gene-level screening in GoCAR uncovered the LIMS1 locus as the top-ranked gene where D-R mismatches associated with death-censored graft loss (DCGL). A previously unreported, intronic, LIMS1 haplotype of 30 SNPs independently associated with DCGL in both cohorts. Haplotype mismatches showed a dosage effect, and minor-allele introduction to major-allele-carrying recipients showed greater hazard of DCGL. The LIMS1 haplotype and the previously reported LIMS1 SNP rs893403 are expression quantitative trait loci (eQTL) in immune cells for GCC2 (not LIMS1), which encodes a protein involved in mannose-6-phosphase receptor (M6PR) recycling. Peripheral blood and T cell transcriptome analyses associated the GCC2 gene and LIMS1 SNPs with the TGF-β1/SMAD pathway, suggesting a regulatory effect. In vitro GCC2 modulation impacted M6PR-dependent regulation of active TGF-β1 and downstream signaling in T cells. Together, our data link LIMS1 locus D-R mismatches to DCGL via GCC2 eQTLs that modulate TGF-β1-dependent effects on T cells.
Collapse
Affiliation(s)
- Zeguo Sun
- Division of Nephrology, Department of Medicine
| | - Zhongyang Zhang
- Department of Genetics and Genomic Science, and
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Khadija Banu
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Ian W. Gibson
- Max Rady college of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Zhengzi Yi
- Division of Nephrology, Department of Medicine
| | | | - Bony De Kumar
- Yale Center for Genomics, New Haven, Connecticut, USA
| | - Anand Reghuvaran
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - John Pell
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas D. Manes
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | | | - Lorenzo Gallon
- Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Philip J. O’Connell
- The Westmead Institute for Medical Research, University of Sydney, New South Wales, Australia
| | | | - Jordan S. Pober
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | | | - Madhav C. Menon
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| |
Collapse
|
|
23
|
Murata T, Hama N, Kamatani T, Mori A, Otsuka R, Wada H, Seino KI. Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance. Am J Transplant 2023; 23:1331-1344. [PMID: 37244443 DOI: 10.1016/j.ajt.2023.05.020] [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: 11/09/2022] [Revised: 05/10/2023] [Accepted: 05/20/2023] [Indexed: 05/29/2023]
Abstract
In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit+Sca-1+Lineage- phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation.
Collapse
Affiliation(s)
- Tomoki Murata
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Naoki Hama
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Tomoki Kamatani
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Akihiro Mori
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Ryo Otsuka
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Haruka Wada
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Ken-Ichiro Seino
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
| |
Collapse
|
|
24
|
Salvadori M. Role of Biomarkers in Detecting Acute Rejection in Kidney Transplantation. TRANSPLANTOLOGY 2023; 4:18-21. [DOI: 10.3390/transplantology4010004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Medicine has evolved from the so-called experience-based medicine to evidence-based medicine, which is now evolving into precision-based medicine [...]
Collapse
Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, 50139 Florence, Italy
| |
Collapse
|
|
25
|
Tambur AR, Bestard O, Campbell P, Chong AS, Barrio MC, Ford ML, Gebel HM, Heidt S, Hickey M, Jackson A, Kosmoliaptsis V, Lefaucheur C, Louis K, Mannon RB, Mengel M, Morris A, Pinelli DF, Reed EF, Schinstock C, Taupin JL, Valenzuela N, Wiebe C, Nickerson P. Sensitization in transplantation: Assessment of Risk 2022 Working Group Meeting Report. Am J Transplant 2023; 23:133-149. [PMID: 36695615 DOI: 10.1016/j.ajt.2022.11.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/20/2022] [Accepted: 11/02/2022] [Indexed: 01/13/2023]
Abstract
The Sensitization in Transplantation: Assessment of Risk workgroup is a collaborative effort of the American Society of Transplantation and the American Society of Histocompatibility and Immunogenetics that aims at providing recommendations for clinical testing, highlights gaps in current knowledge, and proposes areas for further research to enhance histocompatibility testing in support of solid organ transplantation. This report provides updates on topics discussed by the previous Sensitization in Transplantation: Assessment of Risk working groups and introduces 2 areas of exploration: non-human leukocyte antigen antibodies and utilization of human leukocyte antigen antibody testing measurement to evaluate the efficacy of antibody-removal therapies.
Collapse
Affiliation(s)
- Anat R Tambur
- Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA.
| | - Oriol Bestard
- Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Patricia Campbell
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada
| | - Anita S Chong
- Section of Transplantation, Department of Surgery, The University of Chicago, Chicago, Illinois, USA
| | - Martha Crespo Barrio
- Department of Nephrology, Hospital del Mar & Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Mandy L Ford
- Department of Surgery and Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | - Howard M Gebel
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Netherlands
| | - Michelle Hickey
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Annette Jackson
- Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale UMR-S970, Université de Paris, Paris, France
| | - Kevin Louis
- Paris Translational Research Center for Organ Transplantation, Institut national de la santé et de la recherche médicale UMR-S970, Université de Paris, Paris, France
| | - Roslyn B Mannon
- Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Michael Mengel
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada
| | - Anna Morris
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA
| | - David F Pinelli
- Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | | | - Jean-Luc Taupin
- Department of Immunology, Saint Louis Hospital and University Paris-Cité, Paris, France
| | - Nicole Valenzuela
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Chris Wiebe
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Peter Nickerson
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
26
|
Comoli P, Cioni M, Ray B, Tagliamacco A, Innocente A, Caridi G, Bruschi M, Hariharan J, Fontana I, Trivelli A, Magnasco A, Nocco A, Klersy C, Muscianisi S, Ghiggeri GM, Cardillo M, Verrina E, Nocera A, Ginevri F. Anti-glutathione S-transferase theta 1 antibodies correlate with graft loss in non-sensitized pediatric kidney recipients. Front Med (Lausanne) 2022; 9:1035400. [DOI: 10.3389/fmed.2022.1035400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/14/2022] [Indexed: 12/05/2022] Open
Abstract
IntroductionImmunity to Human leukocyte antigen (HLA) cannot explain all cases of ABMR, nor the differences observed in the outcome of kidney recipients with circulating DSAs endowed with similar biologic characteristics. Thus, increasing attention has recently been focused on the role of immunity to non-HLA antigenic targets.MethodsWe analyzed humoral auto- and alloimmune responses to the non-HLA antigen glutathione S-transferase theta 1 (GSTT1), along with development of de novo (dn)HLA-DSAs, in a cohort of 146 pediatric non-sensitized recipients of first kidney allograft, to analyze its role in ABMR and graft loss. A multiplex bead assay was employed to assess GSTT1 antibodies (Abs).ResultsWe observed development of GSTT1 Abs in 71 recipients after transplantation, 16 with MFI > 8031 (4th quartile: Q4 group). In univariate analyses, we found an association between Q4-GSTT1Abs and ABMR and graft loss, suggesting a potential role in inducing graft damage, as GSTT1 Abs were identified within ABMR biopsies of patients with graft function deterioration in the absence of concomitant intragraft HLA-DSAs. HLA-DSAs and GSTT1 Abs were independent predictors of graft loss in our cohort. As GSTT1 Ab development preceded or coincided with the appearance of dnHLA-DSAs, we tested and found that a model with the two combined parameters proved more fit to classify patients at risk of graft loss.DiscussionOur observations on the harmful effects of GSTT1Abs, alone or in combination with HLA-DSAs, add to the evidence pointing to a negative role of allo- and auto-non-HLA Abs on kidney graft outcome.
Collapse
|
|
27
|
Mismatches in Gene Deletions and Kidney-related Proteins as Candidates for Histocompatibility Factors in Kidney Transplantation. Kidney Int Rep 2022; 7:2484-2494. [DOI: 10.1016/j.ekir.2022.08.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
|
|
28
|
Li Y, Nieuwenhuis LM, Keating BJ, Festen EA, de Meijer VE. The Impact of Donor and Recipient Genetic Variation on Outcomes After Solid Organ Transplantation: A Scoping Review and Future Perspectives. Transplantation 2022; 106:1548-1557. [PMID: 34974452 PMCID: PMC9311456 DOI: 10.1097/tp.0000000000004042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/16/2021] [Accepted: 11/25/2021] [Indexed: 11/25/2022]
Abstract
At the outset of solid organ transplantation, genetic variation between donors and recipients was recognized as a major player in mechanisms such as allograft tolerance and rejection. Genome-wide association studies have been very successful in identifying novel variant-trait associations, but have been difficult to perform in the field of solid organ transplantation due to complex covariates, era effects, and poor statistical power for detecting donor-recipient interactions. To overcome a lack of statistical power, consortia such as the International Genetics and Translational Research in Transplantation Network have been established. Studies have focused on the consequences of genetic dissimilarities between donors and recipients and have reported associations between polymorphisms in candidate genes or their regulatory regions with transplantation outcomes. However, knowledge on the exact influence of genetic variation is limited due to a lack of comprehensive characterization and harmonization of recipients' or donors' phenotypes and validation using an experimental approach. Causal research in genetics has evolved from agnostic discovery in genome-wide association studies to functional annotation and clarification of underlying molecular mechanisms in translational studies. In this overview, we summarize how the recent advances and progresses in the field of genetics and genomics have improved the understanding of outcomes after solid organ transplantation.
Collapse
Affiliation(s)
- Yanni Li
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lianne M. Nieuwenhuis
- Department of Surgery, section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Brendan J. Keating
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Eleonora A.M. Festen
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent E. de Meijer
- Department of Surgery, section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
29
|
Lammerts RGM, Altulea D, Hepkema BG, Sanders JS, van den Born J, Berger SP. Antigen and Cell-Based Assays for the Detection of Non-HLA Antibodies. Front Immunol 2022; 13:864671. [PMID: 35603145 PMCID: PMC9122123 DOI: 10.3389/fimmu.2022.864671] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/16/2022] [Indexed: 01/20/2023] Open
Abstract
To date, human leukocyte antigens (HLA) have been the major focus in the approach to acute and chronic antibody-mediated rejection (AMBR) in solid-organ transplantation. However, evidence from the clinic and published studies has shown that non-HLA antibodies, particularly anti-endothelial cell antibodies (AECAs), are found either in the context of AMBR or synergistically in the presence of donor-specific anti-HLA antibodies (DSA). Numerous studies have explored the influence of AECAs on clinical outcomes, yet the determination of the exact clinical relevance of non-HLA antibodies in organ transplantation is not fully established. This is due to highly heterogeneous study designs including differences in testing methods and outcome measures. Efforts to develop reliable and sensitive diagnostic non-HLA antibody tests are continuously made. This is essential considering the technical difficulties of non-HLA antibody assays and the large variation in reported incidences of antibodies. In addition, it is important to take donor specificity into account in order to draw clinically relevant conclusions from non-HLA antibody assays. Here, we provide an overview of non-HLA solid-phase and cell-based crossmatch assays for use in solid-organ transplantation that are currently available, either in a research setting or commercially.
Collapse
Affiliation(s)
- Rosa G. M. Lammerts
- Transplantation Immunology, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
- *Correspondence: Rosa G. M. Lammerts,
| | - Dania Altulea
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Bouke G. Hepkema
- Transplantation Immunology, Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jan-Stephan Sanders
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jacob van den Born
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Stefan P. Berger
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| |
Collapse
|
|
30
|
Van Loon E, Lamarthée B, Barba T, Claes S, Coemans M, de Loor H, Emonds MP, Koshy P, Kuypers D, Proost P, Senev A, Sprangers B, Tinel C, Thaunat O, Van Craenenbroeck AH, Schols D, Naesens M. Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings. Front Immunol 2022; 13:818569. [PMID: 35281018 PMCID: PMC8904423 DOI: 10.3389/fimmu.2022.818569] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/10/2022] [Indexed: 12/17/2022] Open
Abstract
Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation.
Collapse
Affiliation(s)
- Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Thomas Barba
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Sandra Claes
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Leuven Biostatistics and Statistical Bioinformatics Centre, Department of Public Health and Primary Care, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Henriette de Loor
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Marie-Paule Emonds
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Priyanka Koshy
- Department of Imaging and Pathology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Red Cross-Flanders, Mechelen, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium.,Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital Lyon, Hospices Civils de Lyon, Lyon, France
| | - Amaryllis H Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dominique Schols
- Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.,Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
31
|
Senev A, Ray B, Lerut E, Hariharan J, Heylen C, Kuypers D, Sprangers B, Emonds MP, Naesens M. The Pre-Transplant Non-HLA Antibody Burden Associates With the Development of Histology of Antibody-Mediated Rejection After Kidney Transplantation. Front Immunol 2022; 13:809059. [PMID: 35250981 PMCID: PMC8888449 DOI: 10.3389/fimmu.2022.809059] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/25/2022] [Indexed: 01/03/2023] Open
Abstract
Background Many kidney allografts fail due to the occurrence of antibody-mediated rejection (ABMR), related to donor-specific anti-HLA antibodies (HLA-DSA). However, the histology of ABMR can also be observed in patients without HLA-DSA. While some non-HLA antibodies have been related to the histology of ABMR, it is not well known to what extent they contribute to kidney allograft injury. Here we aimed to investigate the role of 82 different non-HLA antibodies in the occurrence of histology of ABMR after kidney transplantation. Methods We included all patients who underwent kidney transplantation between 2004-2013 in a single center and had biobanked serum. Pre- and post-transplant sera (n=2870) were retrospectively tested for the presence of 82 different non-HLA antibodies using a prototype bead assay on Luminex (Immucor, Inc). A ratio was calculated between the measured MFI value and the cut-off MFI defined by the vendor for each non-HLA target. Results 874 patients had available pretransplant sera and were included in this analysis. Of them, 133 (15.2%) received a repeat kidney allograft, and 100 (11.4%) had pretransplant HLA-DSA. In total, 204 (23.3%) patients developed histology of ABMR after kidney transplantation. In 79 patients (38.7%) the histology of ABMR was explained by pretransplant or de novo HLA-DSA. The multivariable Cox analysis revealed that only the broadly non-HLA sensitized (number of positive non-HLA antibodies) patients and those with the highest total strength of the non-HLA antibodies (total ratios of the positive non-HLA antibodies) were independently associated with increased rates of histology of ABMR after transplantation. Additionally, independent associations were found for antibodies against TUBB (HR=2.40; 95% CI 1.37 – 4.21, p=0.002), Collagen III (HR=1.67; 95% CI 1.08 – 2.58, p=0.02), VCL (HR=2.04; 95% CI 1.12 – 3.71, p=0.02) and STAT6 (HR=1.47; 95% CI 1.01 – 2.15, p=0.04). The overall posttransplant non-HLA autoreactivity was not associated with increased rates of ABMRh. Conclusions This study shows that patients highly and broadly sensitized against non-HLA targets are associated with an increased risk of ABMR histology after kidney transplantations in the absence of HLA-DSA. Also, some pretransplant non‐HLA autoantibodies are individually associated with increased rates of ABMR histology. However, whether these associations are clinically relevant and represent causality, warrants further studies.
Collapse
Affiliation(s)
- Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Bryan Ray
- Immucor Inc., Norcross, GA, United States
| | - Evelyne Lerut
- Department of Imaging and Pathology, University Hospitals Leuven, Leuven, Belgium
| | | | | | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Marie-Paule Emonds
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
32
|
Lebraud E, Eloudzeri M, Rabant M, Lamarthée B, Anglicheau D. Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms. Front Immunol 2022; 13:864730. [PMID: 35392097 PMCID: PMC8980419 DOI: 10.3389/fimmu.2022.864730] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 02/22/2022] [Indexed: 12/26/2022] Open
Abstract
Antibody-mediated rejection (ABMR) is associated with poor transplant outcomes and was identified as a leading cause of graft failure after kidney transplantation. Although the hallmark histological features of ABMR (ABMRh), i.e., microvascular inflammation (MVI), usually correlate with the presence of anti-human leukocyte antigen donor-specific antibodies (HLA-DSAs), it is increasingly recognized that kidney transplant recipients can develop ABMRh in the absence of HLA-DSAs. In fact, 40-60% of patients with overt MVI have no circulating HLA-DSAs, suggesting that other mechanisms could be involved. In this review, we provide an update on the current understanding of the different pathogenic processes underpinning MVI. These processes include both antibody-independent and antibody-dependent mechanisms of endothelial injury and ensuing MVI. Specific emphasis is placed on non-HLA antibodies, for which we discuss the ontogeny, putative targets, and mechanisms underlying endothelial toxicity in connection with their clinical impact. A better understanding of these emerging mechanisms of allograft injury and all the effector cells involved in these processes may provide important insights that pave the way for innovative diagnostic tools and highly tailored therapeutic strategies.
Collapse
Affiliation(s)
- Emilie Lebraud
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France
| | - Maëva Eloudzeri
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France
| | - Marion Rabant
- Department of Renal Pathology, Necker Hospital, AP-HP, Paris, France
| | - Baptiste Lamarthée
- Université Bourgogne Franche-Comté, EFS BFC, Inserm UMR1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Dijon, France
| | - Dany Anglicheau
- Necker-Enfants Malades Institute, Inserm U1151, Université de Paris, Department of Nephrology and Kidney Transplantation, Necker Hospital, AP-HP, Paris, France
| |
Collapse
|
|
33
|
Zorn E, See SB. Antibody Responses to Minor Histocompatibility Antigens After Solid Organ Transplantation. Transplantation 2022; 106:749-753. [PMID: 34699457 PMCID: PMC8957520 DOI: 10.1097/tp.0000000000003969] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Antibody-mediated rejection (AMR) is a major barrier to long-term graft survival following solid organ transplantation (SOT). Major histocompatibility antigens mismatched between donor and recipient are well-recognized targets of humoral alloimmunity in SOT and thought to drive most cases of AMR. In contrast, the implication of minor histocompatibility antigens (mHAs) in AMR has not been fully investigated, and their clinical relevance remains controversial. Recent technological advances, allowing for genome-wide comparisons between donors and recipients, have uncovered novel, polymorphic mHA targets with potential influence on the graft outcome following SOT. Here, we review these latest studies relating to mHAs and discuss their clinical significance.
Collapse
Affiliation(s)
- Emmanuel Zorn
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032
| | - Sarah B. See
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032
| |
Collapse
|
|
34
|
Jethwani P, Rao A, Bow L, Menon MC. Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms. Front Immunol 2022; 13:822353. [PMID: 35432337 PMCID: PMC9012490 DOI: 10.3389/fimmu.2022.822353] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/03/2022] [Indexed: 12/22/2022] Open
Abstract
Despite significant improvement in the rates of acute allograft rejection, proportionate improvements in kidney allograft longevity have not been realized, and are a source of intense research efforts. Emerging translational data and natural history studies suggest a role for anti-donor immune mechanisms in a majority of cases of allograft loss without patient death, even when overt evidence of acute rejection is not identified. At the level of the donor and recipient genome, differences in highly polymorphic HLA genes are routinely evaluated between donor and recipient pairs as part of organ allocation process, and utilized for patient-tailored induction and maintenance immunosuppression. However, a growing body of data have characterized specific variants in donor and recipient genes, outside of HLA loci, that induce phenotypic changes in donor organs or the recipient immune system, impacting transplant outcomes. Newer mechanisms for “mismatches” in these non-HLA loci have also been proposed during donor–recipient genome interactions with transplantation. Here, we review important recent data evaluating the role of non-HLA genetic loci and genome-wide donor-recipient mismatches in kidney allograft outcomes.
Collapse
Affiliation(s)
- Priyanka Jethwani
- Department of Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Arundati Rao
- Department of Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Laurine Bow
- Department of Surgery, Yale University School of Medicine, New Haven, CT, United States
| | - Madhav C. Menon
- Department of Medicine, Yale University School of Medicine, New Haven, CT, United States
- *Correspondence: Madhav C. Menon,
| |
Collapse
|
|
35
|
Kamatani T, Otsuka R, Murata T, Wada H, Takahashi T, Mori A, Murata S, Taniguchi H, Seino KI. Evaluation of immunosuppression protocols for MHC-matched allogeneic iPS cell-based transplantation using a mouse skin transplantation model. Inflamm Regen 2022; 42:4. [PMID: 35105370 PMCID: PMC8809003 DOI: 10.1186/s41232-021-00190-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/22/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Off-the-shelf major histocompatibility complex (MHC)-matched iPS cells (iPSC) can potentially initiate host immune responses because of the existence of numerous minor antigens. To suppress allo-immune responses, combination of immunosuppressants is usually used, but its efficacy to the allogeneic iPSC-based transplantation has not been precisely evaluated. METHODS Three transplantation models were used in this study; MHC-matched, minor antigen-mismatched mouse skin or iPSC-graft transplantation, and fully allogeneic human iPSC-derived liver organoid transplantation in immune-humanized mice. The recipients were treated with triple drugs combination (TDC; tacrolimus, methylprednisolone, and mycophenolate mofetil) or co-stimulatory molecule blockade (CB) therapy with some modifications. Graft survival as well as anti-donor T and B cell responses was analyzed. RESULTS In the mouse skin transplantation model, immunological rejection caused by the minor antigen-mismatch ranged from mild to severe according to the donor-recipient combination. The TDC treatment could apparently control the mild skin graft rejection when combined with a transient T cell depletion, but unexpected anti-donor T or B cell response was observed. On the other hand, CB therapy, particularly when combined with rapamycin treatment, was capable of attenuating both mild and severe skin graft rejection and allowing them to survive long-term without any unfavorable anti-donor immune responses. The efficacy of the CB therapy was confirmed in both mouse and human iPSC-derived graft transplantation. CONCLUSIONS The findings suggest that the CB-based treatment seems suitable to well manage the MHC-matched allogeneic iPSC-based transplantation. The TDC-based treatment may be also used to suppress the rejection, but screening of its severity prior to the transplantation seems to be needed.
Collapse
Affiliation(s)
- Tomoki Kamatani
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Sapporo, Hokkaido, 060-0815, Japan
| | - Ryo Otsuka
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Sapporo, Hokkaido, 060-0815, Japan
| | - Tomoki Murata
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Sapporo, Hokkaido, 060-0815, Japan
| | - Haruka Wada
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Sapporo, Hokkaido, 060-0815, Japan
| | - Takeshi Takahashi
- Central Institute for Experimental Animals (CIEA), Kawasaki, 210-0821, Japan
| | - Akihiro Mori
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
- Department of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan
| | - Ken-Ichiro Seino
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Sapporo, Hokkaido, 060-0815, Japan.
| |
Collapse
|
|
36
|
Ba R, Geffard E, Douillard V, Simon F, Mesnard L, Vince N, Gourraud PA, Limou S. Surfing the Big Data Wave: Omics Data Challenges in Transplantation. Transplantation 2022; 106:e114-e125. [PMID: 34889882 DOI: 10.1097/tp.0000000000003992] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
In both research and care, patients, caregivers, and researchers are facing a leap forward in the quantity of data that are available for analysis and interpretation, marking the daunting "big data era." In the biomedical field, this quantitative shift refers mostly to the -omics that permit measuring and analyzing biological features of the same type as a whole. Omics studies have greatly impacted transplantation research and highlighted their potential to better understand transplant outcomes. Some studies have emphasized the contribution of omics in developing personalized therapies to avoid graft loss. However, integrating omics data remains challenging in terms of analytical processes. These data come from multiple sources. Consequently, they may contain biases and systematic errors that can be mistaken for relevant biological information. Normalization methods and batch effects have been developed to tackle issues related to data quality and homogeneity. In addition, imputation methods handle data missingness. Importantly, the transplantation field represents a unique analytical context as the biological statistical unit is the donor-recipient pair, which brings additional complexity to the omics analyses. Strategies such as combined risk scores between 2 genomes taking into account genetic ancestry are emerging to better understand graft mechanisms and refine biological interpretations. The future omics will be based on integrative biology, considering the analysis of the system as a whole and no longer the study of a single characteristic. In this review, we summarize omics studies advances in transplantation and address the most challenging analytical issues regarding these approaches.
Collapse
Affiliation(s)
- Rokhaya Ba
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
- Département Informatique et Mathématiques, Ecole Centrale de Nantes, Nantes, France
| | - Estelle Geffard
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
| | - Venceslas Douillard
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
| | - Françoise Simon
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
- Mount Sinai School of Medicine, New York, NY
| | - Laurent Mesnard
- Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France
- Sorbonne Université, Paris, France
| | - Nicolas Vince
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
| | - Pierre-Antoine Gourraud
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
| | - Sophie Limou
- Université de Nantes, Centre Hospitalier Universitaire Nantes, Institute of Health and Medical Research, Centre de Recherche en Transplantation et Immunologie, UMR 1064, Institut de Transplantation Urologie-Néphrologie, Nantes, France
- Département Informatique et Mathématiques, Ecole Centrale de Nantes, Nantes, France
| |
Collapse
|
|
37
|
Callemeyn J, Lamarthée B, Koenig A, Koshy P, Thaunat O, Naesens M. Allorecognition and the spectrum of kidney transplant rejection. Kidney Int 2021; 101:692-710. [PMID: 34915041 DOI: 10.1016/j.kint.2021.11.029] [Citation(s) in RCA: 84] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 10/05/2021] [Accepted: 11/08/2021] [Indexed: 12/18/2022]
Abstract
Detection of mismatched human leukocyte antigens by adaptive immune cells is considered as the main cause of transplant rejection, leading to either T-cell mediated rejection or antibody-mediated rejection. This canonical view guided the successful development of immunosuppressive therapies and shaped the diagnostic Banff classification for kidney transplant rejection that is used in clinics worldwide. However, several observations have recently emerged that question this dichotomization between T-cell mediated rejection and antibody-mediated rejection, related to heterogeneity in the serology, histology, and prognosis of the rejection phenotypes. In parallel, novel insights were obtained concerning the dynamics of donor-specific anti-human leukocyte antigen antibodies, the immunogenicity of donor-recipient non-human leukocyte antigen mismatches, and the autoreactivity against self-antigens. Moreover, the potential of innate allorecognition was uncovered, as exemplified by natural killer cell-mediated microvascular inflammation through missing self, and by the emerging evidence on monocyte-driven allorecognition. In this review, we highlight the gaps in the current classification of rejection, provide an overview of the expanding insights into the mechanisms of allorecognition, and critically appraise how these could improve our understanding and clinical approach to kidney transplant rejection. We argue that consideration of the complex interplay of various allorecognition mechanisms can foster a more integrated view of kidney transplant rejection and can lead to improved risk stratification, targeted therapies, and better outcome after kidney transplantation.
Collapse
Affiliation(s)
- Jasper Callemeyn
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Baptiste Lamarthée
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Necker-Enfants Malades Institute, French National Institute of Health and Medical Research (INSERM) Unit 1151, Paris, France
| | - Alice Koenig
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France; Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Priyanka Koshy
- Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, University Lyon, Lyon, France; Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France; Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France
| | - Maarten Naesens
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
| |
Collapse
|
|
38
|
Lamarthée B, Burger C, Leclaire C, Lebraud E, Zablocki A, Morin L, Lebreton X, Charreau B, Snanoudj R, Charbonnier S, Blein T, Hardy M, Zuber J, Satchell S, Gallazzini M, Terzi F, Legendre C, Taupin JL, Rabant M, Tinel C, Anglicheau D. CRISPR/Cas9-Engineered HLA-Deleted Glomerular Endothelial Cells as a Tool to Predict Pathogenic Non-HLA Antibodies in Kidney Transplant Recipients. J Am Soc Nephrol 2021; 32:3231-3251. [PMID: 35167486 PMCID: PMC8638404 DOI: 10.1681/asn.2021050689] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/20/2021] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND After kidney transplantation, donor-specific antibodies against human leukocyte antigen donor-specific antibodies (HLA-DSAs) drive antibody-mediated rejection (ABMR) and are associated with poor transplant outcomes. However, ABMR histology (ABMRh) is increasingly reported in kidney transplant recipients (KTRs) without HLA-DSAs, highlighting the emerging role of non-HLA antibodies (Abs). METHODS W e designed a non-HLA Ab detection immunoassay (NHADIA) using HLA class I and II-deficient glomerular endothelial cells (CiGEnCΔHLA) that had been previously generated through CRISPR/Cas9-induced B2M and CIITA gene disruption. Flow cytometry assessed the reactivity to non-HLA antigens of pretransplantation serum samples from 389 consecutive KTRs. The intensity of the signal observed with the NHADIA was associated with post-transplant graft histology assessed in 951 adequate biopsy specimens. RESULTS W e sequentially applied CRISPR/Cas9 to delete the B2M and CIITA genes to obtain a CiGEnCΔHLA clone. CiGEnCΔHLA cells remained indistinguishable from the parental cell line, CiGEnC, in terms of morphology and phenotype. Previous transplantation was the main determinant of the pretransplantation NHADIA result (P<0.001). Stratification of 3-month allograft biopsy specimens (n=298) according to pretransplantation NHADIA tertiles demonstrated that higher levels of non-HLA Abs positively correlated with increased glomerulitis (P=0.002), microvascular inflammation (P=0.003), and ABMRh (P=0.03). A pretransplantation NHADIA threshold of 1.87 strongly discriminated the KTRs with the highest risk of ABMRh (P=0.005, log-rank test). A multivariate Cox model confirmed that NHADIA status and HLA-DSAs were independent, yet synergistic, predictors of ABMRh. CONCLUSION The NHADIA identifies non-HLA Abs and strongly predicts graft endothelial injury independent of HLA-DSAs.
Collapse
Affiliation(s)
- Baptiste Lamarthée
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Carole Burger
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Charlotte Leclaire
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Emilie Lebraud
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Aniela Zablocki
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Lise Morin
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Xavier Lebreton
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Béatrice Charreau
- Center for Research in Transplantation and Immunology, INSERM UMR1064, IHU CESTI, LabEx IGO and LabEx Transplantex, Nantes University, Nantes, France
| | - Renaud Snanoudj
- Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, AP-HP, LabEx Transplantex, INSERM U1160, University Paris Diderot, Paris, France
| | - Soëli Charbonnier
- Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM U1163, University of Paris, Paris, France
| | - Tifanie Blein
- Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM U1163, University of Paris, Paris, France
| | - Mélanie Hardy
- Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, AP-HP, INSERM U976, IRSL, University of Paris, Paris, France
| | - Julien Zuber
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France,Laboratory of Human Lymphohematopoiesis, Imagine Institute, INSERM U1163, University of Paris, Paris, France
| | - Simon Satchell
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Morgan Gallazzini
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Fabiola Terzi
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Christophe Legendre
- Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Jean Luc Taupin
- Immunology and Histocompatibility Laboratory, Saint-Louis Hospital, AP-HP, INSERM U976, IRSL, University of Paris, Paris, France
| | - Marion Rabant
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France,Department of Pathology, Necker Hospital, AP-HP, Paris, France
| | - Claire Tinel
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France
| | - Dany Anglicheau
- Necker-Enfants Malades Institute, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151, University of Paris, Paris, France,Department of Nephrology and Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| |
Collapse
|
|
39
|
Filippone EJ, Gulati R, Farber JL. Noninvasive Assessment of the Alloimmune Response in Kidney Transplantation. Adv Chronic Kidney Dis 2021; 28:548-560. [PMID: 35367023 DOI: 10.1053/j.ackd.2021.08.002] [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: 04/09/2021] [Revised: 05/28/2021] [Accepted: 08/26/2021] [Indexed: 11/11/2022]
Abstract
Transplantation remains the optimal mode of kidney replacement therapy, but unfortunately long-term graft survival after 1 year remains suboptimal. The main mechanism of chronic allograft injury is alloimmune, and current clinical monitoring of kidney transplants includes measuring serum creatinine, proteinuria, and immunosuppressive drug levels. The most important biomarker routinely monitored is human leukocyte antigen (HLA) donor-specific antibodies (DSAs) with the frequency based on underlying immunologic risk. HLA-DSA should be measured if there is graft dysfunction, immunosuppression minimization, or nonadherence. Antibody strength is semiquantitatively estimated as mean fluorescence intensity, with titration studies for equivocal cases and for following response to treatment. Determination of in vitro C1q or C3d positivity or HLA-DSA IgG subclass analysis remains of uncertain significance, but we do not recommend these for routine use. Current evidence does not support routine monitoring of non-HLA antibodies except anti-angiotensin II type 1 receptor antibodies when the phenotype is appropriate. The monitoring of both donor-derived cell-free DNA in blood or gene expression profiling of serum and/or urine may detect subclinical rejection, although mainly as a supplement and not as a replacement for biopsy. The optimal frequency and cost-effectiveness of using these noninvasive assays remain to be determined. We review the available literature and make recommendations.
Collapse
|
|
40
|
Arthur VL, Li Z, Cao R, Oetting WS, Israni AK, Jacobson PA, Ritchie MD, Guan W, Chen J. A Multi-Marker Test for Analyzing Paired Genetic Data in Transplantation. Front Genet 2021; 12:745773. [PMID: 34721531 PMCID: PMC8548646 DOI: 10.3389/fgene.2021.745773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 09/23/2021] [Indexed: 12/02/2022] Open
Abstract
Emerging evidence suggests that donor/recipient matching in non-HLA (human leukocyte antigen) regions of the genome may impact transplant outcomes and recognizing these matching effects may increase the power of transplant genetics studies. Most available matching scores account for either single-nucleotide polymorphism (SNP) matching only or sum these SNP matching scores across multiple gene-coding regions, which makes it challenging to interpret the association findings. We propose a multi-marker Joint Score Test (JST) to jointly test for association between recipient genotype SNP effects and a gene-based matching score with transplant outcomes. This method utilizes Eigen decomposition as a dimension reduction technique to potentially increase statistical power by decreasing the degrees of freedom for the test. In addition, JST allows for the matching effect and the recipient genotype effect to follow different biological mechanisms, which is not the case for other multi-marker methods. Extensive simulation studies show that JST is competitive when compared with existing methods, such as the sequence kernel association test (SKAT), especially under scenarios where associated SNPs are in low linkage disequilibrium with non-associated SNPs or in gene regions containing a large number of SNPs. Applying the method to paired donor/recipient genetic data from kidney transplant studies yields various gene regions that are potentially associated with incidence of acute rejection after transplant.
Collapse
Affiliation(s)
- Victoria L. Arthur
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Zhengbang Li
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
- Departments of Statistics, Central China Normal University, Wuhan, China
| | - Rui Cao
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States
| | - William S. Oetting
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States
| | - Ajay K. Israni
- Minneapolis Medical Research Foundation, Minneapolis, MN, United States
- Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, United States
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States
| | - Pamala A. Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States
| | - Marylyn D. Ritchie
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States
| | - Jinbo Chen
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| |
Collapse
|
|
41
|
Increased Autoantibodies Against Ro/SS-A, CENP-B, and La/SS-B in Patients With Kidney Allograft Antibody-mediated Rejection. Transplant Direct 2021; 7:e768. [PMID: 34557585 PMCID: PMC8454907 DOI: 10.1097/txd.0000000000001215] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/02/2021] [Indexed: 01/20/2023] Open
Abstract
Supplemental Digital Content is available in the text. Antibody-mediated rejection (AMR) causes more than 50% of late kidney graft losses. In addition to anti-human leukocyte antigen (HLA) donor-specific antibodies, antibodies against non-HLA antigens are also linked to AMR. Identifying key non-HLA antibodies will improve our understanding of AMR.
Collapse
|
|
42
|
Callemeyn J, Senev A, Coemans M, Lerut E, Sprangers B, Kuypers D, Koenig A, Thaunat O, Emonds MP, Naesens M. Missing Self-Induced Microvascular Rejection of Kidney Allografts: A Population-Based Study. J Am Soc Nephrol 2021; 32:2070-2082. [PMID: 34301794 PMCID: PMC8455279 DOI: 10.1681/asn.2020111558] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/29/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Circulating anti-HLA donor-specific antibodies (HLA-DSA) are often absent in kidney transplant recipients with microvascular inflammation (MVI). Missing self, the inability of donor endothelial cells to provide HLA I-mediated signals to inhibitory killer cell Ig-like receptors (KIRs) on recipient natural killer cells, can cause endothelial damage in vitro, and has been associated with HLA-DSA-negative MVI. However, missing self's clinical importance as a nonhumoral trigger of allograft rejection remains unclear. METHODS In a population-based study of 924 consecutive kidney transplantations between March 2004 and February 2013, we performed high-resolution donor and recipient HLA typing and recipient KIR genotyping. Missing self was defined as the absence of A3/A11, Bw4, C1, or C2 donor genotype, with the presence of the corresponding educated recipient inhibitory KIR gene. RESULTS We identified missing self in 399 of 924 transplantations. Co-occurrence of missing self types had an additive effect in increasing MVI risk, with a threshold at two concurrent types (hazard ratio [HR], 1.78; 95% confidence interval [95% CI], 1.26 to 2.53), independent of HLA-DSA (HR, 5.65; 95% CI, 4.01 to 7.96). Missing self and lesions of cellular rejection were not associated. No HLA-DSAs were detectable in 146 of 222 recipients with MVI; 28 of the 146 had at least two missing self types. Missing self associated with transplant glomerulopathy after MVI (HR, 2.51; 95% CI, 1.12 to 5.62), although allograft survival was better than with HLA-DSA-associated MVI. CONCLUSION Missing self specifically and cumulatively increases MVI risk after kidney transplantation, independent of HLA-DSA. Systematic evaluation of missing self improves understanding of HLA-DSA-negative MVI and might be relevant for improved diagnostic classification and patient risk stratification.
Collapse
Affiliation(s)
- Jasper Callemeyn
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross‐Flanders, Mechelen, Belgium
| | - Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Evelyne Lerut
- Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Ben Sprangers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium,Department of Microbiology, Immunology and Transplantation, Laboratory of Molecular Immunology, KU Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Alice Koenig
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Lyon, France
| | - Olivier Thaunat
- International Center of Infectiology research (CIRI), French Institute of Health and Medical Research (INSERM) Unit 1111, Claude Bernard University Lyon I, National Center for Scientific Research (CNRS) Mixed University Unit (UMR) 5308, Ecole Normale Supérieure de Lyon, University of Lyon, Lyon, France,Lyon-Est Medical Faculty, Claude Bernard University (Lyon 1), Lyon, France,Department of Transplantation, Nephrology and Clinical Immunology, Edouard Herriot Hospital, Lyon, France
| | - Marie-Paule Emonds
- Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross‐Flanders, Mechelen, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
43
|
Abstract
Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell-mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.
Collapse
|
|
44
|
Meliambro K, Li X, Salem F, Yi Z, Sun Z, Chan L, Chung M, Chancay J, Vy HMT, Nadkarni G, Wong JS, Fu J, Lee K, Zhang W, He JC, Campbell KN. Molecular Analysis of the Kidney From a Patient With COVID-19-Associated Collapsing Glomerulopathy. Kidney Med 2021; 3:653-658. [PMID: 33942030 PMCID: PMC8080498 DOI: 10.1016/j.xkme.2021.02.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Recent case reports suggest that coronavirus disease 2019 (COVID-19) is associated with collapsing glomerulopathy in African Americans with apolipoprotein L1 gene (APOL1) risk alleles; however, it is unclear whether disease pathogenesis is similar to HIV-associated nephropathy. RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19-associated collapsing glomerulopathy and APOL1 risk alleles (G1/G1) revealed similar levels of APOL1 and angiotensin-converting enzyme 2 (ACE2) messenger RNA transcripts as compared with 12 control kidney samples downloaded from the GTEx (Genotype-Tissue Expression) Portal. Whole-genome sequencing of the COVID-19-associated collapsing glomerulopathy kidney sample identified 4 indel gene variants, 3 of which are of unknown significance with respect to chronic kidney disease and/or focal segmental glomerulosclerosis. Molecular profiling of the kidney demonstrated activation of COVID-19-associated cell injury pathways such as inflammation and coagulation. Evidence for direct severe acute respiratory syndrome coronavirus 2 infection of kidney cells was lacking, which is consistent with the findings of several recent studies. Interestingly, immunostaining of kidney biopsy sections revealed increased expression of phospho-STAT3 (signal transducer and activator of transcription 3) in both COVID-19-associated collapsing glomerulopathy and HIV-associated nephropathy as compared with control kidney tissue. Importantly, interleukin 6-induced activation of STAT3 may be a targetable mechanism driving COVID-19-associated acute kidney injury.
Collapse
Affiliation(s)
- Kristin Meliambro
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Xuezhu Li
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Nephrology, Shanghai Ninth Hospital, Jiao Tong University Medical School, Shanghai
| | - Fadi Salem
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York
| | - Zhengzi Yi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Zeguo Sun
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Lili Chan
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Miriam Chung
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jorge Chancay
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Ha My T. Vy
- Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York
| | - Girish Nadkarni
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jenny S. Wong
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Jia Fu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Weijia Zhang
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - John C. He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Renal Program, James J Peters VAMC, Bronx, NY
| | - Kirk N. Campbell
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| |
Collapse
|
|
45
|
Coemans M, Senev A, Van Loon E, Lerut E, Sprangers B, Kuypers D, Emonds MP, Verbeke G, Naesens M. The evolution of histological changes suggestive of antibody-mediated injury, in the presence and absence of donor-specific anti-HLA antibodies. Transpl Int 2021; 34:1824-1836. [PMID: 34197662 DOI: 10.1111/tri.13964] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/01/2021] [Accepted: 06/27/2021] [Indexed: 11/26/2022]
Abstract
The interplay between donor-specific anti-HLA antibodies (HLA-DSA), histology of active antibody-mediated rejection (aABMRh ), transplant glomerulopathy (cg) and graft failure in kidney transplantation remains insufficiently understood. We performed a single-center cohort study (n=1000) including 2761 protocol and 833 indication biopsies. Patients with pre-transplant HLA-DSA were more prone to develop aABMRh (OR 22.7, 95% CI, 11.8 - 43.7, p<0.001), cg (OR 5.76, 95% CI, 1.67 - 19.8, p=0.006) and aABMRh/cg (OR 19.5, 95% CI, 10.6 - 35.9, p<0.001). The negative impact of pre-transplant HLA-DSA on graft survival (HR 2.12, 95% CI, 1.41 - 3.20, p<0.001) was partially mediated through aABMRh and cg occurrence. When adjusted for time-dependent HLA-DSA (HR 4.03, 95% CI, 2.21 - 7.15, p=0.002), graft failure was only affected by aABMRh when cg was evident. In HLA-DSA negative patients, aABMRh was associated with impaired graft outcome only when evolving to cg (HR 1.32, 95% CI, 1.07 - 1.61, p=0.008). We conclude that the kinetics of HLA-DSA are important to estimate the rate of graft failure, and that histological follow-up is necessary to discover, often subclinical, ABMR and cg. In the absence of HLA-DSA, patients experience similar histological lesions and the evolution to transplant glomerulopathy associates with impaired graft outcome.
Collapse
Affiliation(s)
- Maarten Coemans
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
| | - Aleksandar Senev
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Evelyne Lerut
- Department of Imaging & Pathology, University Hospitals Leuven, Leuven, Belgium
| | - Ben Sprangers
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Marie-Paule Emonds
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Histocompatibility and Immunogenetics Laboratory, Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Geert Verbeke
- Leuven Biostatistics and Statistical Bioinformatics Centre (L-BioStat), Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.,Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| |
Collapse
|
|
46
|
Lefaucheur C, Louis K, Philippe A, Loupy A, Coates PT. The emerging field of non-human leukocyte antigen antibodies in transplant medicine and beyond. Kidney Int 2021; 100:787-798. [PMID: 34186057 DOI: 10.1016/j.kint.2021.04.044] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/03/2021] [Accepted: 04/21/2021] [Indexed: 12/21/2022]
Abstract
The major medical advances in our knowledge of the human leukocyte antigen (HLA) system have allowed us to uncover several gaps in our understanding of alloimmunity. Although the non-HLA system has long sparked the interest of the transplant community, recognition of the role of immunity to non-HLA antigenic targets has only emerged recently. In this review, we will provide a comprehensive summary of the paradigm-changing concept of immunity to the non-HLA angiotensin II type 1 receptor (AT1R), discovered by Duška Dragun et al., that began from careful bedside clinical observations, to validated detection of anti-AT1R antibodies and lead to clinical intervention. This scientific approach has also allowed the recognition of broader pathogenicity of anti-AT1R antibodies across multiple organ transplants and in other human diseases, the integration of both non-HLA and HLA systems to understand their immunologic effects on organ allografts, and the identification of future directions for therapeutic intervention to modulate immunity to AT1R. Rationally designed successful interventions to target AT1R system provide an exemplar for other non-HLA antibodies to cross borders between medical specialties, will generate new avenues in translational research beyond transplantation, and will foster the development of new and reliable tools to improve our understanding of non-HLA immunity and ultimately allow us to improve patient care.
Collapse
Affiliation(s)
- Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale UMR-S970, Université de Paris, Paris, France; Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
| | - Kevin Louis
- Kidney Transplant Department, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Human Immunology and Immunopathology, Institut National de la santé et de la recherche médicale UMR-976, Université de Paris, Paris, France
| | - Aurélie Philippe
- Department of Nephrology and Critical Care Medicine, Campus Virchow Klinikum, Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale UMR-S970, Université de Paris, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - P Toby Coates
- Discipline of Medicine, School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia; Central Northern Adelaide Renal and Transplantation Service (CNARTS), The Royal Adelaide Hospital, Adelaide, South Australia, Australia
| |
Collapse
|
|
47
|
Oberbauer R, Meyer TW. Precision medicine in transplantation and hemodialysis. Nephrol Dial Transplant 2021; 36:31-36. [PMID: 34153984 PMCID: PMC8216726 DOI: 10.1093/ndt/gfaa367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Indexed: 12/30/2022] Open
Abstract
In kidney transplantation, precision medicine has already entered clinical practice. Donor and recipient human leucocyte antigen (HLA) regions are genotyped in two class 1 and usually three class 2 loci, and the individual degree of sensitization against alloimmune antigens is evaluated by the detection of anti-HLA donor-specific antibodies. Recently, the contribution of non-HLA mismatches to outcomes such as acute T- and B-cell-mediated rejection and even long-term graft survival was described. Tracking of specific alloimmune T- and B-cell clones by next generation sequencing and refinement of the immunogenicity of allo-epitopes specifically in the interaction with HLA and T- and B-cell receptors may further support individualized therapy. Although the choices of maintenance immunosuppression are rather limited, individualization can be accomplished by adjustment of dosing based on these risk predictors. Finally, supplementing histopathology by a transcriptomics analysis allows for a biological interpretation of the histological findings and avoids interobserver variability of results. In contrast to transplantation, the prescription of hemodialysis therapy is far from precise. Guidelines do not consider modifications by age, diet or many comorbid conditions. Patients with residual kidney function routinely receive the same treatment as those without. A major barrier hitherto is the definition of 'adequate' treatment based on urea removal. Kt/Vurea and related parameters neither reflect the severity of uremic symptoms nor predict long-term outcomes. Urea is poorly representative for numerous other compounds that accumulate in the body when the kidneys fail, yet clinicians prescribe treatment based on its measurement. Modern technology has provided the means to identify other solutes responsible for specific features of uremic illness and their measurement will be a necessary step in moving beyond the standardized prescription of hemodialysis.
Collapse
Affiliation(s)
- Rainer Oberbauer
- Klinische Abteilung für Nephrologie und Dialyse, Medical University of
Vienna, Vienna, Austria
| | - Timothy W Meyer
- Department of Medicine, VA Palo Alto HCS and Stanford University,
Palo Alto, CA, USA
| |
Collapse
|
|
48
|
The role of non-HLA antibodies in solid organ transplantation: a complex deliberation. Curr Opin Organ Transplant 2021; 25:536-542. [PMID: 33044346 DOI: 10.1097/mot.0000000000000811] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW There is tremendous interest in understanding when, if, and how non-HLA antibodies contribute to allograft injury. Numerous non-HLA target antigens have been identified and sensitization to these targets have been associated with delayed allograft function, rejection, and allograft failure. This review focuses on the clinical utility of HLA antibody testing, highlighting the strengths and limitations of current clinical studies, and the need for defining characteristics to inform non-HLA antibody pathogenicity. RECENT FINDINGS Clinical studies continue to show associations between non-HLA antibodies and rejection and reduced allograft survival across multiple transplanted organ types. The worst clinical outcomes continue to be observed among recipients testing positive for both non-HLA and donor-specific HLA antibodies. Mechanistic insights from both animal and clinical studies support a model in which tissue injury accompanied by an inflammatory environment influence non-HLA antibody formation and pathogenicity. SUMMARY Immune triggers that lead to non-HLA antibody formation and pathogenicity are complex and poorly understood. The ability of non-HLA antibodies to mediate allograft injury may depend upon their affinity and strength (titer), target specificity, density of the target antigen, and synergy with donor-specific HLA antibodies.
Collapse
|
|
49
|
Caliskan Y, Karahan G, Akgul SU, Mirioglu S, Ozluk Y, Yazici H, Demir E, Dirim AB, Turkmen A, Edwards J, Savran FO, Sever MS, Kiryluk K, Gharavi A, Lentine KL. LIMS1 Risk Genotype and T-Cell Mediated Rejection in Kidney Transplant Recipients. Nephrol Dial Transplant 2021; 36:2120-2129. [PMID: 33909908 DOI: 10.1093/ndt/gfab168] [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: 01/23/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND This study aims to examine the association of LIM Zinc Finger Domain Containing 1 (LIMS1) genotype with allograft rejection in an independent kidney transplant cohort. METHODS We genotyped 841 kidney transplant recipients for LIMS1 rs893403 variant by Sanger sequencing followed by PCR confirmation of the deletion. Recipients who were homozygous for LIMS1 rs893403 genotype GG were compared to AA/AG genotypes. The primary outcome was T-cell mediated (TCMR) or antibody mediated rejection (ABMR) and secondary outcome was allograft loss. RESULTS After a median follow-up of 11.4 years, the rate of TCMR was higher in recipients with the GG (n = 200) compared to AA/AG (n = 641) genotypes [25 (12.5%) vs 35 (5.5%); p = 0.001] while ABMR did not differ by genotype [18 (9.0%) vs 62 (9.7%)]. Recipients with GG genotype had 2.4-times higher risk of TCMR than those who did not have this genotype (adjusted hazard ratio (aHR), 1.442.434.12, p = 0.001). A total of 189 (22.5%) recipients lost their allografts during follow up. Kaplan-Meier estimates of 5-year (94.3% vs. 94.4%, p = 0.99) and 10-year graft survival rates (86.9% vs. 83.4%, p = 0.31) did not differ significantly in those with GG compared to AA/AG groups. CONCLUSIONS Our study demonstrates that recipient LIMS1 risk genotype is associated with increased risk of TCMR after kidney transplantation, confirming the role of LIMS1 locus in allograft rejection. These findings may have clinical implications for the prediction and clinical management of kidney transplant rejection by pretransplant genetic testing of recipients and donors for LIMS1 risk genotype.
Collapse
Affiliation(s)
- Yasar Caliskan
- Division of Nephrology, Saint Louis University, Saint Louis, MO, USA.,Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Gonca Karahan
- Department of Medical Biology, Istanbul University School of Medicine, Turkey.,Leiden University Medical Center, Leiden, The Netherlands
| | - Sebahat Usta Akgul
- Department of Medical Biology, Istanbul University School of Medicine, Turkey
| | - Safak Mirioglu
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Yasemin Ozluk
- Department of Pathology, Istanbul University School of Medicine, Turkey
| | - Halil Yazici
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Erol Demir
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Ahmet B Dirim
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - Aydin Turkmen
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | - John Edwards
- Division of Nephrology, Saint Louis University, Saint Louis, MO, USA
| | - Fatma Oguz Savran
- Department of Medical Biology, Istanbul University School of Medicine, Turkey
| | - Mehmet S Sever
- Division of Nephrology, Istanbul University School of Medicine, Turkey
| | | | - Ali Gharavi
- Division of Nephrology, Columbia University Medical Center, NY, USA
| | - Krista L Lentine
- Division of Nephrology, Saint Louis University, Saint Louis, MO, USA
| |
Collapse
|
|
50
|
Histologic Antibody-Mediated Kidney Allograft Rejection in the Absence of Donor Specific HLA Antibodies. Transplantation 2021; 105:e181-e190. [PMID: 33901113 DOI: 10.1097/tp.0000000000003797] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Histologic antibody-mediated rejection (hAMR) is defined as a kidney allograft biopsy satisfying the first 2 Banff criteria for diagnosing antibody-mediated rejection (AMR): tissue injury and evidence of current/recent antibody interaction with the endothelium. In approximately one-half of such cases, circulating HLA donor specific antibodies (DSA) are not detectable by current methodology at the time of biopsy. Some studies indicated a better prognosis for HLA-DSA-negative cases of hAMR compared to those with detectable HLA-DSA, whereas others found equally poor survival compared to hAMR-negative cases. We reviewed the literature regarding the pathophysiology of HLA-DSA-negative hAMR. We find 3 nonmutually exclusive possibilities: 1) HLA-DSA are involved, but just not detected; 2) non-HLA DSA (allo- or autoantibodies) are pathogenically involved; and/or 3) antibody-independent NK cell activation is mediating the process through "missing self" or other activating mechanisms. These possibilities are discussed in detail. Recommendations regarding the approach to such patients are made. Clearly, more research is necessary regarding the measurement of non-HLA antibodies, recipient/donor NK cell genotyping, and the use of antibody reduction therapy or other immunosuppression in any subset of patients with HLA-DSA-negative hAMR.
Collapse
|