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Diebold M, Vietzen H, Schatzl M, Mayer KA, Haindl S, Heinzel A, Hittmeyer P, Herz CT, Hopfer H, Menter T, Kühner LM, Berger SM, Puchhammer-Stöckl E, Doberer K, Steiger J, Schaub S, Böhmig GA. Functional Natural Killer-cell Genetics and Microvascular Inflammation After Kidney Transplantation: An Observational Cohort Study. Transplantation 2025; 109:860-870. [PMID: 39402708 PMCID: PMC12011434 DOI: 10.1097/tp.0000000000005228] [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: 06/21/2024] [Revised: 08/13/2024] [Accepted: 08/26/2024] [Indexed: 04/23/2025]
Abstract
BACKGROUND Recent evidence highlights the pivotal role of natural killer (NK) cells in allograft rejection. METHODS We explored associations of missing self and gene polymorphisms determining the phenotype and/or functionality of NK cells with microvascular inflammation (MVI) in a single-center cohort of 507 consecutive kidney transplant recipients. Patients were genotyped for killer cell Ig-like receptors and polymorphisms in 4 selected genes ( FCGR3AV/F158 [rs396991], KLRC2wt/del , KLRK1HNK/LNK [rs1049174], and rs9916629-C/T). RESULTS MVI was detected in 69 patients (13.6%). In a proportional odds model, the KLRC2del/del variant reduced MVI risk (odds ratio [OR] 0.26; 95% confidence interval [CI], 0.05-0.93; P = 0.037) independent of donor-specific antibodies, HLA class II eplet mismatch, and number of biopsies. Conversely, missing self (OR 1.40; 95% CI, 1.08-1.80; P = 0.011) and the rs9916629 T/T gene variant increased the risk (OR 1.70; 95% CI, 1.08-2.68; P = 0.021). Graft loss tended to be more frequent among patients with missing self ≥2 (hazard ratio 1.97; 95% CI, 0.89-4.37; P = 0.097), without influence on estimated glomerular filtration trajectories. FCGR3A variants were associated with MVI only in patients with preformed and/or de novo donor-specific antibodies (OR 4.14; 95% CI, 0.99-17.47; P = 0.052). CONCLUSIONS Missing self and NK-cell genetics may contribute to MVI, underscoring the important role of NK cells in transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Hannes Vietzen
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Martina Schatzl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Susanne Haindl
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Andreas Heinzel
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Philip Hittmeyer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Carsten T. Herz
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Helmut Hopfer
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Thomas Menter
- Department of Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Laura M. Kühner
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | - Sarah M. Berger
- Center for Virology, Medical University of Vienna, Vienna, Austria
| | | | - Konstantin Doberer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Jürg Steiger
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Stefan Schaub
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Diebold M, Gauthier PT, Mayer KA, Mackova M, Hinze C, Chang J, Patel UD, Schütz E, Jilma B, Schrezenmeier E, Budde K, Böhmig GA, Halloran PF. Effect of felzartamab on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies. Nat Med 2025:10.1038/s41591-025-03653-3. [PMID: 40301559 DOI: 10.1038/s41591-025-03653-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 03/10/2025] [Indexed: 05/01/2025]
Abstract
A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, Basel, Switzerland
| | - Patrick T Gauthier
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Katharina A Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Martina Mackova
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Christian Hinze
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Jessica Chang
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Uptal D Patel
- Human Immunology Biosciences, South San Francisco, CA, USA
| | | | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Eva Schrezenmeier
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
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3
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Böhmig GA, Loupy A, Sablik M, Naesens M. Microvascular inflammation in kidney allografts: New directions for patient management. Am J Transplant 2025:S1600-6135(25)00170-4. [PMID: 40199388 DOI: 10.1016/j.ajt.2025.03.031] [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: 01/29/2025] [Revised: 03/12/2025] [Accepted: 03/27/2025] [Indexed: 04/10/2025]
Abstract
Microvascular inflammation (MVI) is a key histological feature of immune-mediated injury at the capillary interface of renal allografts, characterized by immune cell infiltration into glomerular and peritubular capillaries. Although traditionally associated with antibody-mediated rejection (AMR), many MVI cases lack detectable donor-specific antibodies (DSA), suggesting the involvement of antibody-independent immune mechanisms or alternative triggers, such as viral infections or ischemia-reperfusion injury. The Banff 2022 scheme introduced a subcategory, "MVI, DSA-negative, C4d-negative," within an overarching AMR or MVI category. This subcategory-similar to AMR-was shown to carry a significant risk of graft failure. Its recognition marks a major advancement, offering a robust framework for investigating the pathophysiology of MVI, which may involve a wide array of overlapping triggers. Emerging evidence from transcriptome analyses highlights natural killer cells as possible effectors, regardless of DSA status. Therapies targeting natural killer cells, particularly the anti-CD38 antibody felzartamab, have shown promising reductions in MVI and molecular injury. Notably, the US Food and Drug Administration has approved an MVI-based primary endpoint for a phase 3 trial evaluating this approach, representing a critical step toward the development of new therapeutics. Recognizing MVI as a multifaceted histological phenotype-driven by diverse triggers-may signal a paradigm shift in transplant medicine.
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Affiliation(s)
- Georg A Böhmig
- Department of Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Alexandre Loupy
- Paris Institute for Transplantation & Organ Regeneration INSERM, Paris, France
| | - Marta Sablik
- Paris Institute for Transplantation & Organ Regeneration INSERM, Paris, France
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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4
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Diebold M, Mayer KA, Hidalgo L, Kozakowski N, Budde K, Böhmig GA. Chronic Rejection After Kidney Transplantation. Transplantation 2025; 109:610-621. [PMID: 39192468 PMCID: PMC11927446 DOI: 10.1097/tp.0000000000005187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/16/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024]
Abstract
In kidney transplantation, ongoing alloimmune processes-commonly triggered by HLA incompatibilities-can trigger chronic transplant rejection, affecting the microcirculation and the tubulointerstitium. Continuous inflammation may lead to progressive, irreversible graft injury, culminating in graft dysfunction and accelerated transplant failure. Numerous experimental and translational studies have delineated a complex interplay of different immune mechanisms driving rejection, with antibody-mediated rejection (AMR) being an extensively studied rejection variant. In microvascular inflammation, a hallmark lesion of AMR, natural killer (NK) cells have emerged as pivotal effector cells. Their essential role is supported by immunohistologic evidence, bulk and spatial transcriptomics, and functional genetics. Despite significant research efforts, a substantial unmet need for approved rejection therapies persists, with many trials yielding negative outcomes. However, several promising therapies are currently under investigation, including felzartamab, a monoclonal antibody targeting the surface molecule CD38, which is highly expressed in NK cells and antibody-producing plasma cells. In an exploratory phase 2 trial in late AMR, this compound has demonstrated potential in resolving molecular and morphologic rejection activity and injury, predominantly by targeting NK cell effector function. These findings inspire hope for effective treatments and emphasize the necessity of further pivotal trials focusing on chronic transplant rejection.
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Affiliation(s)
- Matthias Diebold
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Clinic for Transplantation Immunology and Nephrology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Katharina A. Mayer
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Luis Hidalgo
- HLA Laboratory, Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | | | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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5
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Abbas K, Mubarak M. Expanding role of antibodies in kidney transplantation. World J Transplant 2025; 15:99220. [PMID: 40104192 PMCID: PMC11612895 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.
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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
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6
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Westphal SG, Mannon RB. Biomarkers of Rejection in Kidney Transplantation. Am J Kidney Dis 2025; 85:364-374. [PMID: 39419272 PMCID: PMC11846701 DOI: 10.1053/j.ajkd.2024.07.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/02/2024] [Accepted: 07/26/2024] [Indexed: 10/19/2024]
Abstract
Alloimmune injury is a major cause of long-term kidney allograft failure whether due to functionally stable (subclinical) or overt clinical rejection. These episodes may be mediated by immune cells (cellular rejection) or alloantibody (antibody-mediated rejection). Early recognition of immune injury is needed for timely appropriate intervention to maintain graft functional viability. However, the conventional measure of kidney function (ie, serum creatinine) is insufficient for immune monitoring due to limited sensitivity and specificity for rejection. As a result, there is need for biomarkers that more sensitively detect the immune response to the kidney allograft. Recently, several biomarkers have been clinically implemented into the care of kidney transplant recipients. These biomarkers attempt to achieve multiple goals including (1) more sensitive detection of clinical and subclinical rejection, (2) predicting impending rejection, (3) monitoring for the adequacy of treatment response, and (4) facilitating personalized immunosuppression. In this review, we summarize the findings to date in commercially available biomarkers, along with biomarkers approaching clinical implementation. While we discuss the analytical and clinical validity of these biomarkers, we identify the challenges and limitations to widespread biomarker use, including the need for biomarker-guided prospective studies to establish evidence of clinical utility of these new assays.
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Affiliation(s)
- Scott G Westphal
- Division of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Medical Service, Nebraska Western Iowa Veterans Affairs Health Care System, Omaha, Nebraska
| | - Roslyn B Mannon
- Medical Service, Nebraska Western Iowa Veterans Affairs Health Care System, Omaha, Nebraska.
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7
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Chauveau B, Couzi L, Merville P. The Microscope and Beyond: Current Trends in the Characterization of Kidney Allograft Rejection From Tissue Samples. Transplantation 2025; 109:440-453. [PMID: 39436268 DOI: 10.1097/tp.0000000000005153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2024]
Abstract
The Banff classification is regularly updated to integrate recent advances in the characterization of kidney allograft rejection, gathering novel diagnostic, prognostic, and theragnostic data into a diagnostic and pathogenesis-based framework. Despite ongoing research on noninvasive biomarkers of kidney rejection, the Banff classification remains, to date, biopsy-centered, primarily relying on a semiquantitative histological scoring system that overall lacks reproducibility and granularity. Besides, the ability of histopathological injuries and transcriptomics analyses from bulk tissue to accurately infer the pathogenesis of rejection is questioned. This review discusses findings from past, current, and emerging innovative tools that have the potential to enhance the characterization of allograft rejection from tissue samples. First, the digitalization of pathological workflows and the rise of deep learning should yield more reproducible and quantitative results from routine slides. Additionally, novel histomorphometric features of kidney rejection could be discovered with an overall genuine clinical implementation perspective. Second, multiplex immunohistochemistry enables in-depth in situ phenotyping of cells from formalin-fixed samples, which can decipher the heterogeneity of the immune infiltrate during kidney allograft rejection. Third, transcriptomics from bulk tissue is gradually integrated into the Banff classification, and its specific context of use is currently under extensive consideration. Finally, single-cell transcriptomics and spatial transcriptomics from formalin-fixed and paraffin-embedded samples are emerging techniques capable of producing up to genome-wide data with unprecedented precision levels. Combining all these approaches gives us hope for novel advances that will address the current blind spots of the Banff system.
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Affiliation(s)
- Bertrand Chauveau
- Department of Pathology, Bordeaux University Hospital, Pellegrin Hospital, Place Amélie Raba Léon, Bordeaux, France
- CNRS UMR 5164 ImmunoConcEpT, University of Bordeaux, Bordeaux, France
| | - Lionel Couzi
- CNRS UMR 5164 ImmunoConcEpT, University of Bordeaux, Bordeaux, France
- Department of Nephrology, Transplantation Dialysis, Apheresis, Bordeaux University Hospital, Pellegrin Hospital, Bordeaux, France
| | - Pierre Merville
- CNRS UMR 5164 ImmunoConcEpT, University of Bordeaux, Bordeaux, France
- Department of Nephrology, Transplantation Dialysis, Apheresis, Bordeaux University Hospital, Pellegrin Hospital, Bordeaux, France
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8
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Rabant M, Adam BA, Aubert O, Böhmig GA, Clahsen Van-Groningen M, Cornell LD, de Vries APJ, Huang E, Kozakowski N, Perkowska-Ptasinska A, Riella LV, Rosales IA, Schinstock C, Simmonds N, Thaunat O, Willicombe M. Banff 2022 Kidney Commentary: Reflections and Future Directions. Transplantation 2025; 109:292-299. [PMID: 38886879 DOI: 10.1097/tp.0000000000005112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2024]
Abstract
In September 2022, in Banff, Alberta, Canada, the XVIth Banff meeting, corresponding to the 30th anniversary of the Banff classification, was held, leading to 2 recent publications. Discussions at the Banff meeting focused on proposing improvements to the Banff process as a whole. In line with this, a unique opportunity was offered to a selected group of 16 representatives from the pathology and transplant nephrology community, experts in the field of kidney transplantation, to review these 2 Banff manuscripts. The aim was to provide an insightful commentary, to gauge any prospective influence the proposed changes may have, and to identify any potential areas for future enhancement within the Banff classification. The group expressed its satisfaction with the incorporation of 2 new entities, namely "microvascular inflammation/injury donor-specific antibodies-negative and C4d negative" and "probable antibody-mediated rejection," into category 2. These changes expand the classification, facilitating the capture of more biopsies and providing an opportunity to explore the clinical implications of these lesions further. However, we found that the Banff classification remains complex, potentially hindering its widespread utilization, even if a degree of complexity may be unavoidable given the intricate pathophysiology of kidney allograft pathology. Addressing the histomorphologic diagnosis of chronic active T cell-mediated rejection (CA TCMR), potentially reconsidering a diagnostic-agnostic approach, as for category 2, to inflammation in interstitial fibrosis and tubular atrophy and chronic active T cell-mediated rejection was also an important objective. Furthermore, we felt a need for more evidence before molecular diagnostics could be routinely integrated and emphasized the need for clinical and histologic context determination and the substantiation of its clinical impact through rigorous clinical trials. Finally, our discussions stressed the ongoing necessity for multidisciplinary decision-making regarding patient care.
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Affiliation(s)
- Marion Rabant
- Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Benjamin A Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Olivier Aubert
- Kidney Transplant Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Georg A Böhmig
- Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Marian Clahsen Van-Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus MC Transplant Institute, Rotterdam, the Netherlands
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Lynn D Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Aiko P J de Vries
- Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
- Leiden Transplant Center, Leiden University Medical Center, Leiden, the Netherlands
| | - Edmund Huang
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | | | - Leonardo V Riella
- Nephrology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ivy A Rosales
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Carrie Schinstock
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Naomi Simmonds
- Department of Pathology, Guys and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Olivier Thaunat
- Department of Transplantation, Nephrology and Clinical Immunology, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
| | - Michelle Willicombe
- Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom
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Nankivell BJ, Viswanathan S. Early and Late Microvascular Inflammation Have Differing Etiological Causes and Clinical Expression. Transplantation 2025; 109:376-385. [PMID: 39344003 DOI: 10.1097/tp.0000000000005224] [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] [Indexed: 10/01/2024]
Abstract
BACKGROUND Microvascular inflammation (MVI) is an important pathological feature of antibody-mediated rejection (AMR). How posttransplant time affects its clinicopathological expression is little understood. METHODS This retrospective, single-center study screened 3398 kidney transplant biopsies and dichotomized 202 MVI ≥ 2 (Banff glomerulitis + peritubular capillaritis ≥ 2) samples by 9-mo median incidence time for comparison. RESULTS The prevalence of MVI ≥ 2 was 12.4% in transplant kidneys, which failed more frequently than propensity-matched normal controls (n = 202; P < 0.001). Epidemiological risk factors for early MVI ≥ 2 were delayed graft function, prior AMR, and circulating donor-specific antibodies (DSAs+). Prior recipient sensitization occurred in 72.3%. Early MVI ≥ 2 was classified AMR in 65.3% and cellular rejection in 34.7%, and demonstrated excellent functional recovery and graft survival comparable to normal control kidneys. Late MVI ≥ 2 was predicted by younger (18 = 29 y) age, female recipient, living-donation, prior methylprednisolone, cyclosporine (versus tacrolimus, levels <5 ng/mL), absent antiproliferative therapy, and DSA+ using multivariable epidemiological modeling. Nonadherence caused 49.5%, with iatrogenic minimization responsible for 47.5%, usually for recipient infection. Late MVI ≥ 2 was because of AMR in 93.1%, and characterized by greater interstitial fibrosis, tubular atrophy, complement degradation split-product 4d (C4d) staining of peritubular capillaries+, endothelial C4d staining of glomerular capillaries+, transplant glomerulopathy and vasculopathy scores, DSA strength, and graft failure than early MVI ≥ 2 or normal transplant kidneys. Death-censored graft survival in 149 unique MVI ≥ 2 kidneys was independently determined by nonadherence, serum creatinine, proteinuria, DSA+, Banff C4d staining of peritubular capillaries+, and chronic interstitial fibrosis scores. MVI score and time lost significance using multivariable Cox regression. CONCLUSIONS The changing expression of MVI ≥ 2 over time is best explained by differences in underimmunosuppression and microvascular injury from AMR impacting allograft function and survival.
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Affiliation(s)
- Brian J Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, NSW, Australia
| | - Seethalakshmi Viswanathan
- Department of Tissue Pathology and Diagnostic Oncology, ICPMR, Westmead Hospital, Westmead, NSW, Australia
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10
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Madill-Thomsen KS, Gauthier PT, Abouljoud M, Bhati C, Bruno D, Ciszek M, Durlik M, Feng S, Foroncewicz B, Grąt M, Jurczyk K, Levitsky J, McCaughan G, Maluf D, Montano-Loza A, Moonka D, Mucha K, Myślak M, Perkowska-Ptasińska A, Piecha G, Reichman T, Tronina O, Wawrzynowicz-Syczewska M, Zeair S, Halloran PF. Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study. Transplantation 2025:00007890-990000000-00971. [PMID: 39780312 DOI: 10.1097/tp.0000000000005269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
BACKGROUND Initial analysis of liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov; unique identifier NCT03193151) using rejection-associated transcripts failed to find an antibody-mediated rejection state (ie, rich in natural killer [NK] cells and with interferon-gamma effects). We recently developed an optimization strategy in lung transplants that isolated an NK cell-enriched rejection-like (NKRL) state that was molecularly distinct from T cell-mediated rejection (TCMR). Here we apply the same strategy to a liver transplant biopsy population. METHODS We used this strategy to search for a molecular NKRL state in 765 consented liver transplant biopsies collected at participating international centers for gold-standard histology and molecular assessment by genome-wide microarrays. Validation through a training set-test set approach of an optimized selection of variables as inputs into unsupervised rejection classification identified an NKRL state in livers. RESULTS The full model classified 765 biopsies into the following molecular phenotypes, characterized by their gene expression: no-rejection 54%, TCMR 16%, NKRL 13%, and injury 16%. Top TCMR transcripts were expressed in effector T cells; top NKRL transcripts were almost exclusively expressed in NK cells; and both had increased interferon-γ-inducible transcripts, which were more pronounced in TCMR. Most TCMR biopsies had significant parenchymal injury, molecular fibrosis, and abnormal biochemistry. NKRL biopsies had no excess of injury, fibrosis, or biochemistry abnormalities. CONCLUSIONS Optimized rejection algorithms indicate that some liver transplants manifest an NKRL state that is well tolerated in the short term postbiopsy and with minimal injury and relatively normal biochemistry, while also underscoring the potential of TCMR to produce extensive parenchymal injury.
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Affiliation(s)
| | | | - Marwan Abouljoud
- Department of Surgery, Henry Ford Hospital, Virginia Commonwealth University, Richmond, VA
| | | | - David Bruno
- Department of Surgery, University of Maryland, Baltimore, MD
| | - Michał Ciszek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Magdalena Durlik
- Department of Transplant Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | - Bartosz Foroncewicz
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Jurczyk
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Josh Levitsky
- Department of Medicine, Northwestern University, Chicago, IL
| | - Geoff McCaughan
- Australian National Liver Transplant Unit, Centenary Research Institute, Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia
| | - Daniel Maluf
- Department of Surgery, University of Maryland, Baltimore, MD
| | | | - Dilip Moonka
- Department of Surgery, Henry Ford Hospital, Virginia Commonwealth University, Richmond, VA
| | - Krzysztof Mucha
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
| | - Marek Myślak
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | | | - Grzegorz Piecha
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | | | - Olga Tronina
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Marta Wawrzynowicz-Syczewska
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
| | - Samir Zeair
- Department of Infectious Diseases, Hepatology and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland
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11
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Nankivell BJ, Taverniti A, Viswanathan S, Ronquillo J, Carroll R, Sharma A. The relationship of microvascular inflammation with antibody-mediated rejection in kidney transplantation. Am J Transplant 2025; 25:115-126. [PMID: 39084463 DOI: 10.1016/j.ajt.2024.07.023] [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: 03/11/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024]
Abstract
Microvascular inflammation (MVI) is a key diagnostic feature of antibody-mediated rejection (AMR); however, recipients without donor-specific antibodies (DSA) defy etiologic classification using C4d staining of peritubular capillaries (C4dptc) and conventional DSA assignment. We evaluated MVI ≥ 2 (Banff g + ptc ≥ 2) using Banff 2019 AMR (independent of MVI ≥ 2 but including C4dptc) with unconventional endothelial C4d staining of glomerular capillaries (C4dglom) and - arterial endothelium and/or intima (C4dart) using tissue immunoperoxidase, shared-eplet and subthreshold DSA (median fluorescence intensity, [MFI] 100-499), and capillary ultrastructure from 3398 kidney transplant samples for evidence of AMR. MVI ≥ 2 (n = 202 biopsies) from 149 kidneys (12.4% prevalence) correlated with DSA+, C4dptc+, C4dglom+, Banff cg, i, t, ti scores, serum creatinine, proteinuria, and graft failure compared with 202 propensity score matched normal controls. The laboratory reported DSA- MVI ≥ 2 (MFI ≥500) occurred in 34.7%; however, subthreshold (28.6%), eplet-directed (51.4%), and/or misclassified anti-Human leukocyte antigen (HLA) DSA (12.9%) were identified in 67.1% by forensic reanalysis, with vascular C4d+ staining in 67.1%, and endothelial abnormalities in 57.1%, totaling 87.1%. Etiologic analysis attributed 62.9% to AMR (77.8% for MVI with negative reported DSA [DSA- MVI ≥2] with glomerulitis) and pure T cellular rejection in 37.1%. C4dptc-DSA- MVI ≥ 2 was unrecognized AMR in 48.0%. Functional outcomes and graft survival were comparable to normal controls. We concluded that DSA- MVI ≥ 2 frequently signified a mild "borderline" phenotype of AMR which was recognizable using novel serologic and pathological techniques.
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Affiliation(s)
- Brian J Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia.
| | - Anne Taverniti
- New South Wales Transplantation and Immunogenetics, Australian Red Cross, LifeBlood, New South Wales, Australia
| | | | - John Ronquillo
- Tissue Pathology and Diagnostic Oncology, ICPMR, Sydney, Australia
| | - Robert Carroll
- New South Wales Transplantation and Immunogenetics, Australian Red Cross, LifeBlood, New South Wales, Australia
| | - Ankit Sharma
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
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12
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Halloran PF, Madill-Thomsen KS, Böhmig G, Bromberg J, Budde K, Barner M, Mackova M, Chang J, Einecke G, Eskandary F, Gupta G, Myślak M, Viklicky O, Akalin E, Alhamad T, Anand S, Arnol M, Baliga R, Banasik M, Bingaman A, Blosser CD, Brennan D, Chamienia A, Chow K, Ciszek M, de Freitas D, Dęborska-Materkowska D, Debska-Ślizień A, Djamali A, Domański L, Durlik M, Fatica R, Francis I, Fryc J, Gill J, Gill J, Glyda M, Gourishankar S, Grenda R, Gryczman M, Hruba P, Hughes P, Jittirat A, Jurekovic Z, Kamal L, Kamel M, Kant S, Kasiske B, Kojc N, Konopa J, Lan J, Mannon R, Matas A, Mazurkiewicz J, Miglinas M, Müller T, Narins S, Naumnik B, Patel A, Perkowska-Ptasińska A, Picton M, Piecha G, Poggio E, Bloudíčkova SR, Samaniego-Picota M, Schachtner T, Shin S, Shojai S, Sikosana MLN, Slatinská J, Smykal-Jankowiak K, Solanki A, Veceric Haler Ž, Vucur K, Weir MR, Wiecek A, Włodarczyk Z, Yang H, Zaky Z. Subthreshold rejection activity in many kidney transplants currently classified as having no rejection. Am J Transplant 2025; 25:72-87. [PMID: 39117038 DOI: 10.1016/j.ajt.2024.07.034] [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: 05/08/2024] [Revised: 06/19/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024]
Abstract
Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems.
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Affiliation(s)
- Philip F Halloran
- Department of Medicine, Division of Nephrology & Transplantation Immunology, University of Alberta, Canada
| | | | - Georg Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Austria
| | | | - Klemens Budde
- Department of Nephrology, Charite-Medical University of Berlin, Germany
| | | | | | | | - Gunilla Einecke
- Department of Nephrology, Medical University of Hannover, Germany
| | - Farsad Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Austria
| | - Gaurav Gupta
- Department of Internal Medicine, Division of Nephrology, Virginia Commonwealth University, USA
| | - Marek Myślak
- Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation SPWSZ Hospital, Pomeranian Medical University, Poland
| | - Ondrej Viklicky
- Department of Nephrology and Transplant Center, Institute for Experimental and Clinical Medicine, Czech Republic
| | - Enver Akalin
- Albert Einstein College of Medicine, Montefiore Medical Center, USA
| | - Tarek Alhamad
- Division of Nephrology, Washington University at St. Louis, USA
| | | | - Miha Arnol
- Department of Nephrology, University of Ljubljana, Slovenia
| | | | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Medical University of Wrocław, Poland
| | - Adam Bingaman
- Department of Surgery, Methodist Transplant and Specialty Hospital, USA
| | | | - Daniel Brennan
- Department of Medicine, Johns Hopkins University School of Medicine, USA
| | - Andrzej Chamienia
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Poland
| | - Kevin Chow
- Department of Nephrology, The Royal Melbourne Hospital, Australia
| | - Michał Ciszek
- Department of Immunology, Transplantology and Internal Diseases, Warsaw Medical University, Poland
| | - Declan de Freitas
- Department of Renal Research, Manchester Royal Infirmary, United Kingdom
| | | | - Alicja Debska-Ślizień
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Poland
| | | | - Leszek Domański
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, Poland
| | - Magdalena Durlik
- Department of Transplantology, Immunology, Nephrology and Internal Diseases, Warsaw Medical University, Poland
| | - Richard Fatica
- Department of Kidney Medicine, Cleveland Clinic Foundation, USA
| | | | - Justyna Fryc
- 1st Department of Nephrology and Transplantation With Dialysis Unit, Medical University in Bialystok, Poland
| | | | | | | | - Sita Gourishankar
- Department of Medicine, Division of Nephrology & Transplantation Immunology, University of Alberta, Canada
| | - Ryszard Grenda
- Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Poland
| | - Marta Gryczman
- Department of Nephrology and Kidney Transplantation, Pomeranian Medical University, Poland
| | - Petra Hruba
- Department of Nephrology, Institute for Experimental and Clinical Medicine, Czech Republic
| | - Peter Hughes
- Department of Nephrology, The Royal Melbourne Hospital, Australia
| | | | - Zeljka Jurekovic
- Renal Replacement Therapy, Department of Nephrology, University Hospital Merkur, Croatia
| | - Layla Kamal
- Division of Nephrology, Department of Medicine, Virginia Commonwealth University, USA
| | | | - Sam Kant
- Division of Nephrology & Comprehensive Transplant Center, Department of Medicine, Johns Hopkins University School of Medicine, USA
| | | | - Nika Kojc
- Department of Pathology, University of Ljubljana, Slovenia
| | - Joanna Konopa
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdańsk, Poland
| | | | - Roslyn Mannon
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, USA
| | - Arthur Matas
- Department of Surgery, Division of Transplantation, University on Minnesota, USA
| | | | - Marius Miglinas
- Nephrology and Kidney Transplantation Unit, Nephrology Center, Vilnius University Hospital Santaros Klinikos, Lithuania
| | - Thomas Müller
- Nephrology Department, University Hospital Zurich, Switzerland
| | | | - Beata Naumnik
- 1st Department of Nephrology and Transplantation With Dialysis Unit, Medical University in Bialystok, Poland
| | | | | | - Michael Picton
- Department of Renal Medicine, Manchester Royal Infirmary, United Kingdom
| | - Grzegorz Piecha
- Department of Nephrology, Transplantation and Internal Medicine, Silesian Medical University, Poland
| | - Emilio Poggio
- Department of Kidney Medicine, Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, USA
| | | | | | - Thomas Schachtner
- Department of Surgery and Transplantation, University Hospital Zurich, Switzerland
| | - Sung Shin
- Department of Laboratory Medicine, University of Ulsan College of Medicine/Assan Medical Center, South Korea
| | - Soroush Shojai
- Division of Nephrology, Department of Medicine, University of Alberta, USA
| | - Majid L N Sikosana
- Department of Medicine, Division of Nephrology & Transplantation Immunology, University of Alberta, Canada
| | - Janka Slatinská
- Department of Nephrology, Institute for Experimental and Clinical Medicine, Czech Republic
| | | | | | | | - Ksenija Vucur
- Department of Nephrology, University Hospital Merkur, Croatia
| | - Matthew R Weir
- Department of Medicine, Division of Nephrology, University of Maryland, USA
| | - Andrzej Wiecek
- Department of Nephrology, Transplantation and Internal Medicine, Silesian Medical University, Poland
| | | | - Harold Yang
- Department of Surgery, PinnacleHealth Transplant Associates, USA
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13
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Hruba P, Klema J, Mrazova P, Girmanova E, Jaklova K, Voska L, Kment M, Mackova M, Osickova K, Hanzal V, Halloran PF, Viklicky O. Transcriptomic Signatures of Antibody-mediated Rejection in Early Biopsies With Negative Histology in HLA-incompatible Kidney Transplantation. Transplant Direct 2025; 11:e1741. [PMID: 39687512 PMCID: PMC11649270 DOI: 10.1097/txd.0000000000001741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 12/18/2024] Open
Abstract
Background Presensitized patients with circulating donor-specific antibodies (DSAs) before transplantation are at risk for antibody-mediated rejection (AMR). Peritransplant desensitization mitigates but does not eliminate the alloimmune response. We examined the possibility that subthreshold AMR activity undetected by histology could be operating in some early biopsies. Methods Transcriptome of kidney allograft biopsies performed within the first month in presensitized patients (DSA+) who had received desensitization and did not develop active/probable AMR by histology (R-) was compared with biopsies showing active/probable AMR (R+/DSA+). As negative controls, biopsies without rejection by histology in patients without DSA at transplantation were used (R-/DSA-). RNA sequencing from biopsies selected from the biobank was used in cohort 1 (n = 32) and microarray, including the molecular microscope (Molecular Microscope Diagnostic System [MMDx]) algorithm, in recent cohort 2 (n = 30). Results The transcriptome of R-/DSA+ was similar to R+/DSA+ as these groups differed in 14 transcripts only. Contrarily, large differences were found between both DSA+ groups and negative controls. Fast gene set enrichment analyses showed upregulation of the immune system in both DSA+ groups (gene ontology terms: adaptive immune response, humoral immune response, antigen receptor-mediated signaling, and B-cell receptor signaling or complement activation) when compared with negative controls. MMDx assessment in cohort 2 classified 50% of R-/DSA+ samples as AMR and found no differences in AMR molecular scores between R+ and R- DSA+ groups. In imlifidase desensitization, MMDx series showed a gradual increase in AMR scores over time. Conclusions Presensitized kidney transplant recipients exhibited frequent molecular calls of AMR in biopsy-based transcript diagnostics despite desensitization therapy and negative histology.
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Affiliation(s)
- Petra Hruba
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jiri Klema
- Department of Computer Science, Czech Technical University, Prague, Czech Republic
| | - Petra Mrazova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Eva Girmanova
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Katerina Jaklova
- Department of Immunogenetics, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ludek Voska
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Martin Kment
- Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Martina Mackova
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Klara Osickova
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vladimir Hanzal
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Philip F. Halloran
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
| | - Ondrej Viklicky
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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14
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Robertson H, Kim HJ, Li J, Robertson N, Robertson P, Jimenez-Vera E, Ameen F, Tran A, Trinh K, O'Connell PJ, Yang JYH, Rogers NM, Patrick E. Decoding the hallmarks of allograft dysfunction with a comprehensive pan-organ transcriptomic atlas. Nat Med 2024; 30:3748-3757. [PMID: 38890530 PMCID: PMC11645273 DOI: 10.1038/s41591-024-03030-6] [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: 07/10/2023] [Accepted: 04/29/2024] [Indexed: 06/20/2024]
Abstract
The pathogenesis of allograft (dys)function has been increasingly studied using 'omics'-based technologies, but the focus on individual organs has created knowledge gaps that neither unify nor distinguish pathological mechanisms across allografts. Here we present a comprehensive study of human pan-organ allograft dysfunction, analyzing 150 datasets with more than 12,000 samples across four commonly transplanted solid organs (heart, lung, liver and kidney, n = 1,160, 1,241, 1,216 and 8,853 samples, respectively) that we leveraged to explore transcriptomic differences among allograft dysfunction (delayed graft function, acute rejection and fibrosis), tolerance and stable graft function. We identified genes that correlated robustly with allograft dysfunction across heart, lung, liver and kidney transplantation. Furthermore, we developed a transfer learning omics prediction framework that, by borrowing information across organs, demonstrated superior classifications compared to models trained on single organs. These findings were validated using a single-center prospective kidney transplant cohort study (a collective 329 samples across two timepoints), providing insights supporting the potential clinical utility of our approach. Our study establishes the capacity for machine learning models to learn across organs and presents a transcriptomic transplant resource that can be employed to develop pan-organ biomarkers of allograft dysfunction.
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Affiliation(s)
- Harry Robertson
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Hani Jieun Kim
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Computational Systems Biology Group, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, New South Wales, Australia
- Kinghorn Cancer Centre and Cancer Research Theme, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
| | - Jennifer Li
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Nicholas Robertson
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China
| | - Paul Robertson
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Elvira Jimenez-Vera
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Farhan Ameen
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Andy Tran
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
| | - Katie Trinh
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
| | - Philip J O'Connell
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Jean Y H Yang
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China
| | - Natasha M Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia
- Department of Renal and Transplantation Medicine, Westmead Hospital, Westmead, New South Wales, Australia
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - Ellis Patrick
- School of Mathematics and Statistics, The University of Sydney, Camperdown, New South Wales, Australia.
- Sydney Precision Data Science Centre, The University of Sydney, Camperdown, New South Wales, Australia.
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
- Charles Perkins Centre, The University of Sydney, Camperdown, New South Wales, Australia.
- Laboratory of Data Discovery for Health Limited (D24H), Science Park, Hong Kong SAR, China.
- Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
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15
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Benning L, Bestard O. Shedding Light on Microvascular Inflammation: Understanding Outcomes, But What Sparks the Flame? Transpl Int 2024; 37:14032. [PMID: 39659965 PMCID: PMC11628253 DOI: 10.3389/ti.2024.14032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024]
Affiliation(s)
- Louise Benning
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d’Hebrón University Hospital, Barcelona, Spain
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16
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Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [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: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
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Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
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17
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Ruan DF, Fribourg M, Yuki Y, Park YH, Martin MP, Yu H, Kelly GC, Lee B, de Real RM, Lee R, Geanon D, Kim-Schulze S, Chun N, Cravedi P, Carrington M, Heeger PS, Horowitz A. High-dimensional analysis of NK cells in kidney transplantation uncovers subsets associated with antibody-independent graft dysfunction. JCI Insight 2024; 9:e185687. [PMID: 39388279 PMCID: PMC11601574 DOI: 10.1172/jci.insight.185687] [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: 08/08/2024] [Accepted: 09/24/2024] [Indexed: 10/12/2024] Open
Abstract
Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.
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Affiliation(s)
- Dan Fu Ruan
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
| | - Miguel Fribourg
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Yuko Yuki
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Yeon-Hwa Park
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Maureen P. Martin
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Haocheng Yu
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
| | - Geoffrey C. Kelly
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Brian Lee
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Ronaldo M. de Real
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Rachel Lee
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Daniel Geanon
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Seunghee Kim-Schulze
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Nicholas Chun
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paolo Cravedi
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Mary Carrington
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Peter S. Heeger
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Amir Horowitz
- Department of Immunology and Immunotherapy
- Department of Oncological Sciences
- The Marc and Jennifer Lipschultz Precision Immunology Institute
- Tisch Cancer Institute, and
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18
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Bajaj V, Kashif A, Singh V, Sharma S, Venkatesan S. Glomerulitis in T cell-mediated renal allograft rejection and antibody-mediated rejection histology in the absence of donor-specific antibodies heralds a similar clinico-morphologic pattern of injury to an antibody-mediated rejection: A systematic review. Med J Armed Forces India 2024; 80:620-631. [PMID: 39990525 PMCID: PMC11842912 DOI: 10.1016/j.mjafi.2024.08.017] [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: 08/15/2024] [Accepted: 08/28/2024] [Indexed: 02/25/2025] Open
Abstract
The morphologic finding of transplant glomerulitis (g) forms important evidence of microvascular injury. Besides antibody-mediated rejection (ABMR), this morphological feature is also seen in acute cellular rejection (ACR) and vasculitis but not included in the grading criteria for cellular rejection. A systematic review was thus conducted to summarize the current evidence and shed light on the quantum of impetus to be given to this finding when encountered during evaluation of renal biopsies. Out of a total of 13 studies selected, 06 studies supported the histologic finding of glomerulitis in ACR and non-DSA ABMR morphologies with variable incidence ranging from 15 to 21%. Seven studies supported glomerulitis as an independent prognostic marker for graft outcome at 1 year post transplant with or without DSA with highest HR reported of 4.52 and lowest being 01. Reviewing the present literature revealed interesting insights into occurrence, nature, molecular expression, role in glomerular injury and long-term outcomes with glomerulitis. It is recommended to approach the treatment of such lesions with heightened caution, as there appear to be elevated rates of graft failure, delayed graft function and Transplant glomerulopathy.
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Affiliation(s)
- Varun Bajaj
- Assistant Professor, Department of Pathology, Armed Forces Medical College, Pune, India
| | - A.W. Kashif
- Professor, Department of Pathology, Armed Forces Medical College, Pune, India
| | - Vikram Singh
- Assistant Professor, Department of Pathology, Armed Forces Medical College, Pune, India
| | - Surabhi Sharma
- Senior Resident (Community Medicine), Army Institute of Cardiothoracic Sciences, Pune, India
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19
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Dandonneau J, François A, Bertrand D, Candon S, de Nattes T. Systematic Biopsy-Based Transcriptomics and Diagnosis of Antibody-Mediated Kidney Transplant Rejection in Clinical Practice. Clin J Am Soc Nephrol 2024; 19:1169-1179. [PMID: 39012712 PMCID: PMC11390017 DOI: 10.2215/cjn.0000000000000490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 07/10/2024] [Indexed: 07/18/2024]
Abstract
Key Points Impact of biopsy-based transcriptomics in clinical practice is still unclear. Biopsy-based transcriptomics is indicated in a significant proportion of kidney transplant biopsies for the diagnosis of antibody-mediated rejection. Biopsy-based transcriptomics is useful for antibody-mediated rejection diagnosis in clinical practice. Background To diagnose kidney transplant antibody-mediated rejection (AMR), biopsy-based transcriptomics can substitute for some histological criteria according to the Banff classification. However, clinical accessibility of these assays is still limited. Here, we aimed to evaluate the impact of integrating a routine-compatible molecular assay for the diagnosis of AMR in clinical practice. Methods All biopsies performed in our center between 2013 and 2017 were retrospectively included. These biopsies were classified into three groups: AMR biopsies which displayed the full Banff criteria of AMR independently of biopsy-based transcriptomics; undetermined for AMR biopsies which did not meet AMR histological criteria, but would have been considered as AMR if biopsy-based transcriptomics had been positive; and control biopsies which showed no features of rejection. Results Within the inclusion period, 342 biopsies had a complete Banff scoring. Thirty-six of the biopsies already met AMR criteria, and 43 of 306 (14%) were considered as undetermined for AMR. Among these biopsies, 24 of 43 (56%) had a molecular signature of AMR, reclassifying them into the AMR category. Five-year death-censored survival of these biopsies was unfavorable and statistically equivalent to that of the AMR category (P = 0.22), with 15 of 24 (63%) graft loss. Conclusions A significant proportion of biopsies could benefit from a biopsy-based transcriptomics for AMR diagnosis according to the Banff classification. Using a routine-compatible molecular tool, more than the half of these biopsies were reclassified as AMR and associated with poor allograft survival.
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Affiliation(s)
| | | | | | - Sophie Candon
- Univ Rouen Normandie, INSERM U1234, CHU Rouen, Immunology Department, F-76000 Rouen, France
| | - Tristan de Nattes
- Univ Rouen Normandie, INSERM U1234, CHU Rouen, Nephrology Department, F-76000 Rouen, France
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20
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Harmacek D, Weidmann L, Castrezana Lopez K, Schmid N, Korach R, Bortel N, von Moos S, Rho E, Helmchen B, Gaspert A, Schachtner T. Molecular diagnosis of antibody-mediated rejection: Evaluating biopsy-based transcript diagnostics in the presence of donor-specific antibodies but without microvascular inflammation, a single-center descriptive analysis. Am J Transplant 2024; 24:1652-1663. [PMID: 38548057 DOI: 10.1016/j.ajt.2024.03.034] [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: 10/10/2023] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/19/2024]
Abstract
Biopsy-based transcript diagnostics may identify molecular antibody-mediated rejection (AMR) when microvascular inflammation (MVI) is absent. In this single-center cohort, biopsy-based transcript diagnostics were validated in 326 kidney allograft biopsies. A total of 71 histological AMR and 35 T cell-mediated rejection (TCMR) cases were identified as molecular AMR and TCMR in 55% and 63%, respectively. Among 121 cases without MVI (glomerulitis + peritubular capillaritis = 0), 45 (37%) donor-specific antibody (DSA)-positive and 76 (63%) DSA-negative cases were analyzed. Twenty-one out of the 121 (17%) cases showed borderline changes, or TCMR, while BK nephropathy was excluded. None of the 45 DSA-positive patients showed molecular AMR. Among 76 DSA-negative patients, 2 had mixed molecular AMR/TCMR. All-AMR phenotype scores (sum of R4-R6) exhibited median values of 0.13 and 0.12 for DSA-positive and DSA-negative patients, respectively (P = .84). A total of 13% (6/45) DSA-positive and 11% (8/76) DSA-negative patients showed an all-AMR phenotype score > 0.30 (P = .77). Patients with a higher all-AMR phenotype score showed 33% more histologic TCMR (P = .005). The median all-AMR phenotype scores of glomerular basement membrane double contours = 0 and glomerular basement membrane double contours > 0 biopsies were 0.12 and 0.10, respectively (P = .35). Biopsy-based transcript diagnostics did not identify molecular AMR in cases without MVI. Follow-up biopsies and outcome data should evaluate the clinical relevance of subthreshold molecular alterations.
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Affiliation(s)
- Dusan Harmacek
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Lukas Weidmann
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | | | - Nicolas Schmid
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Raphael Korach
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Nicola Bortel
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Seraina von Moos
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Elena Rho
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Birgit Helmchen
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Ariana Gaspert
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Schachtner
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland.
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21
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Agrawal A, Balakrishnan S, Gandhi MJ, Alexander MP, Cornell L, Bentall AJ, Kukla A, Stegall M, Schinstock CA. Highly Sensitized Candidates Remain at Risk for Microvascular Inflammation Even When Donor-specific Antibody Is Avoided: A Matched Cohort Study. Transplantation 2024; 108:1986-1993. [PMID: 38578704 DOI: 10.1097/tp.0000000000005011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
BACKGROUND Microvascular inflammation (MVI) is a key feature of antibody-mediated rejection (AMR) among patients with HLA donor-specific antibody (DSA), but MVI at AMR thresholds (Banff glomerulitis [g] + peritubular capillaritis [ptc] score ≥ 2) without DSA has been increasingly recognized. We aimed to determine the incidence of MVI among highly sensitized kidney transplant recipients without DSA. METHODS We performed a single-center, retrospective, matched cohort study comparing outcomes of kidney transplant recipients with cPRA ≥90% with preexisting DSA (n = 49), cPRA ≥90% without preexisting DSA (n = 47), and matched controls with cPRA = 0 without preexisting DSA (n = 49). Controls were matched by age, donor type, and transplant date. Indication and surveillance biopsies combined with annual de novo DSA screening were obtained. RESULTS Kidney transplant recipients with a cPRA ≥90% and no evidence of preexisting or de novo DSA had a higher incidence of MVI (glomerulitis + peritubular capillaritis ≥ 2) than patients with cPRA = 0 [35% (17/49) versus 12% (6/49), P = 0.0003] over a median (interquartile range) follow-up of 5 (4-6) y posttransplant. Among this cPRA ≥90% group without DSA, MVI persisted in 54% of cases on follow-up biopsy (7/13), and 24% (4/13) of cases developed transplant glomerulopathy (Banff cg score > 0). CONCLUSIONS Highly sensitized transplant recipients have a high incidence of persistent and progressive MVI, even without DSA. The mechanisms underlying these histologic features needs to be elucidated, but this information is important to consider when making decisions about transplantation among highly sensitized individuals.
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Affiliation(s)
- Amogh Agrawal
- Department of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
| | | | - Manish J Gandhi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Mariam P Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Lynn Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Andrew J Bentall
- Department of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
- Division of Hypertension and Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Aleksandra Kukla
- Department of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
- Division of Hypertension and Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, MN
| | - Mark Stegall
- Department of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
| | - Carrie A Schinstock
- Department of Transplant Surgery, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
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22
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Thaunat O. Natural killer cell-mediated innate microvascular rejection. Nat Rev Nephrol 2024; 20:489-490. [PMID: 38898355 DOI: 10.1038/s41581-024-00862-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Affiliation(s)
- Olivier Thaunat
- CIRI, INSERM U1111, Université Claude Bernard Lyon I, CNRS UMR5308, Ecole Normale Supérieure de Lyon, Univ. Lyon, Lyon, France.
- Hospices Civils de Lyon, Edouard Herriot Hospital, Department of Transplantation, Nephrology and Clinical Immunology, Lyon, France.
- Claude Bernard University (Lyon 1), Villeurbanne, France.
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23
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Vaulet T, Callemeyn J, Lamarthée B, Antoranz A, Debyser T, Koshy P, Anglicheau D, Colpaert J, Gwinner W, Halloran PF, Kuypers D, Tinel C, Van Craenenbroeck A, Van Loon E, Marquet P, Bosisio F, Naesens M. The Clinical Relevance of the Infiltrating Immune Cell Composition in Kidney Transplant Rejection. J Am Soc Nephrol 2024; 35:886-900. [PMID: 38640017 PMCID: PMC11230711 DOI: 10.1681/asn.0000000000000350] [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: 12/04/2023] [Accepted: 04/02/2024] [Indexed: 04/21/2024] Open
Abstract
Key Points The estimated composition of immune cells in kidney transplants correlates poorly with the primary rejection categories defined by Banff criteria. Spatial cell distribution could be coupled with a detailed cellular composition to assess causal triggers for allorecognition. Intragraft CD8temra cells showed strong and consistent association with graft failure, regardless of the Banff rejection phenotypes. Background The link between the histology of kidney transplant rejection, especially antibody-mediated rejection, T-cell–mediated rejection, and mixed rejection, and the types of infiltrating immune cells is currently not well charted. Cost and technical complexity of single-cell analysis hinder large-scale studies of the relationship between cell infiltrate profiles and histological heterogeneity. Methods In this cross-sectional study, we assessed the composition of nine intragraft immune cell types by using a validated kidney transplant–specific signature matrix for deconvolution of bulk transcriptomics in three different kidney transplant biopsy datasets (N =403, N =224, N =282). The association and discrimination of the immune cell types with the Banff histology and the association with graft failure were assessed individually and with multivariable models. Unsupervised clustering algorithms were applied on the overall immune cell composition and compared with the Banff phenotypes. Results Banff-defined rejection was related to high presence of CD8+ effector T cells, natural killer cells, monocytes/macrophages, and, to a lesser extent, B cells, whereas CD4+ memory T cells were lower in rejection compared with no rejection. Estimated intragraft effector memory–expressing CD45RA (TEMRA) CD8+ T cells were strongly and consistently associated with graft failure. The large heterogeneity in immune cell composition across rejection types prevented supervised and unsupervised methods to accurately recover the Banff phenotypes solely on the basis of immune cell estimates. The lack of correlation between immune cell composition and Banff-defined rejection types was validated using multiplex immunohistochemistry. Conclusions Although some specific cell types (FCGR3A + myeloid cells, CD14 + monocytes/macrophages, and NK cells) partly discriminated between rejection phenotypes, the overall estimated immune cell composition of kidney transplants was ill-related to main Banff-defined rejection categories and added to the Banff lesion scoring and evaluation of rejection severity. The estimated intragraft CD8temra cells bore strong and consistent association with graft failure and were independent of Banff-grade rejection.
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Affiliation(s)
- Thibaut Vaulet
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Jasper Callemeyn
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, 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, KU Leuven, Leuven, Belgium
- EFS, INSERM, UMR RIGHT, Université de Franche-Comté, Besançon, France
| | - Asier Antoranz
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | - Tim Debyser
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Priyanka Koshy
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
- Inserm U1151, Necker Enfants-Malades Institute, Université Paris Cité, Paris, France
| | - Jill Colpaert
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
| | - Wilfried Gwinner
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Philip F. Halloran
- Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Dirk Kuypers
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Claire Tinel
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- EFS, INSERM, UMR RIGHT, Université de Franche-Comté, Besançon, France
- Department of Nephrology and Kidney Transplantation, Dijon University Hospital, Dijon, France
| | - Amaryllis Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Elisabet Van Loon
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Pierre Marquet
- Department of Pharmacology and Transplantation, Inserm U1248, Limoges University Hospital, University of Limoges, Limoges, France
| | - Francesca Bosisio
- Department of Imaging and Pathology, Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Nephrology and Kidney Transplantation Research Group, KU Leuven, Leuven, Belgium
- Department of Nephrology and Kidney Transplantation, University Hospitals Leuven, Leuven, Belgium
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24
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Kozakowski N. [Update kidney allograft pathology : A better depiction of microvascular inflammation]. PATHOLOGIE (HEIDELBERG, GERMANY) 2024; 45:269-276. [PMID: 38649466 PMCID: PMC11199282 DOI: 10.1007/s00292-024-01328-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND The Banff Foundation produces recommendations for classifying various lesions in renal allografts. Experts gather to update the classification every other year based on new scientific and clinical evidence. OBJECTIVES This article presents the most important changes incorporated into the new recommendations after the last Banff conference. MATERIALS AND METHODS The author of this article personally took part in the Banff conference and the subsequent survey, reported on the activities of a Banff working group (peritubular capillaritis) on-site, and contributed to drafting the recently published meeting report. RESULTS Lesions of antibody-mediated kidney allograft rejection (AMR), especially microvascular inflammation, have been part of the diagnostic algorithm for over 20 years. Experts advocated for a simplified AMR algorithm and mindful inclusion of molecular pathological data in the clinicopathological reflection regarding therapeutic decision. A new, more descriptive diagnostic entity-microvascular inflammation, C4d negative and DSA negative-has been introduced into the AMR category to acknowledge this histological constellation and motivate research into this pathophysiologically and immunologically probably different phenotype. CONCLUSIONS The Banff classification provides a structure for diagnosing kidney transplant pathology. Regular updates serve to adapt to ever-growing knowledge about alloimmunity. Particular challenges are capturing the complexity of various immunological scenarios and ensuring an understandable representation of these in a pathology report.
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Affiliation(s)
- Nicolas Kozakowski
- Klinisches Institut für Pathologie, Medizinische Universität Wien, Währinger Gürtel 18-20, 1090, Wien, Österreich.
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25
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Hinze C, Lovric S, Halloran PF, Barasch J, Schmidt-Ott KM. Epithelial cell states associated with kidney and allograft injury. Nat Rev Nephrol 2024; 20:447-459. [PMID: 38632381 PMCID: PMC11660082 DOI: 10.1038/s41581-024-00834-0] [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] [Accepted: 03/27/2024] [Indexed: 04/19/2024]
Abstract
The kidney epithelium, with its intricate arrangement of highly specialized cell types, constitutes the functional core of the organ. Loss of kidney epithelium is linked to the loss of functional nephrons and a subsequent decline in kidney function. In kidney transplantation, epithelial injury signatures observed during post-transplantation surveillance are strong predictors of adverse kidney allograft outcomes. However, epithelial injury is currently neither monitored clinically nor addressed therapeutically after kidney transplantation. Several factors can contribute to allograft epithelial injury, including allograft rejection, drug toxicity, recurrent infections and postrenal obstruction. The injury mechanisms that underlie allograft injury overlap partially with those associated with acute kidney injury (AKI) and chronic kidney disease (CKD) in the native kidney. Studies using advanced transcriptomic analyses of single cells from kidney or urine have identified a role for kidney injury-induced epithelial cell states in exacerbating and sustaining damage in AKI and CKD. These epithelial cell states and their associated expression signatures are also observed in transplanted kidney allografts, suggesting that the identification and characterization of transcriptomic epithelial cell states in kidney allografts may have potential clinical implications for diagnosis and therapy.
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Affiliation(s)
- Christian Hinze
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Svjetlana Lovric
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada
- Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, Alberta, Canada
| | - Jonathan Barasch
- Division of Nephrology, Columbia University, New York City, NY, USA
| | - Kai M Schmidt-Ott
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
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26
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Balakrishnan S, Alexander MP, Schinstock C. Challenges and opportunities for designing clinical trials for antibody mediated rejection. FRONTIERS IN TRANSPLANTATION 2024; 3:1389005. [PMID: 38993760 PMCID: PMC11235363 DOI: 10.3389/frtra.2024.1389005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 04/25/2024] [Indexed: 07/13/2024]
Abstract
Significant progress has been made in kidney transplantation, with 1-year graft survival nearing 95%. However, long-term allograft survival remains suboptimal, with a 10-year overall graft survival rate of only 53.6% for deceased donor transplant recipients. Chronic active antibody-mediated rejection (ABMR) is a leading cause of death-censored graft loss, yet no therapy has demonstrated efficacy in large, randomized trials, despite substantial investment from pharmaceutical companies. Several clinical trials aimed to treat chronic ABMR in the past decade have yielded disappointing results or were prematurely terminated, attributed to factors including incomplete understanding of disease mechanisms, heterogeneous patient populations with comorbidities, slow disease progression, and limited patient numbers. This review aims to discuss opportunities for improving retrospective and prospective studies of ABMR, focusing on addressing heterogeneity, outcome measurement, and strategies to enhance patient enrollment to inform study design, data collection, and reporting.
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Affiliation(s)
- Suryanarayanan Balakrishnan
- Division of Hypertension and Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States
| | - Mariam P. Alexander
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
| | - Carrie Schinstock
- Division of Hypertension and Nephrology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States
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27
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Madill-Thomsen K, Halloran P. Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope® Diagnostic System (MMDx). Clin Sci (Lond) 2024; 138:663-685. [PMID: 38819301 PMCID: PMC11147747 DOI: 10.1042/cs20220530] [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: 02/22/2024] [Revised: 04/26/2024] [Accepted: 05/02/2024] [Indexed: 06/01/2024]
Abstract
There is a major unmet need for improved accuracy and precision in the assessment of transplant rejection and tissue injury. Diagnoses relying on histologic and visual assessments demonstrate significant variation between expert observers (as represented by low kappa values) and have limited ability to assess many biological processes that produce little histologic changes, for example, acute injury. Consensus rules and guidelines for histologic diagnosis are useful but may have errors. Risks of over- or under-treatment can be serious: many therapies for transplant rejection or primary diseases are expensive and carry risk for significant adverse effects. Improved diagnostic methods could alleviate healthcare costs by reducing treatment errors, increase treatment efficacy, and serve as useful endpoints for clinical trials of new agents that can improve outcomes. Molecular diagnostic assessments using microarrays combined with machine learning algorithms for interpretation have shown promise for increasing diagnostic precision via probabilistic assessments, recalibrating standard of care diagnostic methods, clarifying ambiguous cases, and identifying potentially missed cases of rejection. This review describes the development and application of the Molecular Microscope® Diagnostic System (MMDx), and discusses the history and reasoning behind many common methods, statistical practices, and computational decisions employed to ensure that MMDx scores are as accurate and precise as possible. MMDx provides insights on disease processes and highly reproducible results from a comparatively small amount of tissue and constitutes a general approach that is useful in many areas of medicine, including kidney, heart, lung, and liver transplants, with the possibility of extrapolating lessons for understanding native organ disease states.
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Affiliation(s)
- Katelynn S. Madill-Thomsen
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, AB, Canada
| | - Philip F. Halloran
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, AB, Canada
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28
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Mella A, Lavacca A, Dodoi DT, Presta R, Fop F, Campagna M, Manzione AM, Dolla C, Gallo E, Abbasciano I, Gai C, Camussi G, Barreca A, Caorsi C, Giovinazzo G, Biancone L. Absence of IL-6 Receptor Blockade Effect on the Outcomes of Transplant Glomerulopathy in the Absence of Anti-HLA Donor-specific Antibodies. Transplant Direct 2024; 10:e1638. [PMID: 38769985 PMCID: PMC11104724 DOI: 10.1097/txd.0000000000001638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 03/03/2024] [Accepted: 03/07/2024] [Indexed: 05/22/2024] Open
Abstract
Background Transplant glomerulopathy (TG) is the hallmark of chronic antibody-mediated rejection but often occurs without anti-HLA donor-specific antibodies (DSAs) in the assumption that other DSAs may be the effectors of the tissue injury. Recently, we reported a positive effect of interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ) in TG/DSA+. In the present study, we investigate the effect of TCZ in a cohort of TG cases without detectable anti-HLA DSAs. Methods Single-center retrospective analysis of TG cases without anti-HLA DSAs (TG/DSA) treated with TCZ for chronic antibody-mediated rejection as first-line therapy evaluated through clinical, protocol biopsies, and gene expression analyses was included. Results Differently from TG/DSA+, TG/DSA- showed a progressive reduction in the estimated glomerular filtration rate at 12 mo and after that with no significant modification in microvascular inflammation or C4d+. No upregulation in tight junction protein-1, aldo-keto reductase family 1 member C3, and calcium/calmodulin-dependent serine protein kinase, documented in TG/DSA+, was noted in post-TCZ biopsies. The reduction of microvascular inflammation was associated with natural killer-cell reduction in TG/DSA+, whereas TG/DSA- tends to maintain or increase periglomerular/interstitial infiltration. Conclusions In the absence of anti-HLA DSAs, TG behavior seems not to be modified by IL-6 receptor blockade. These results are at variance with observational studies and previous trials with IL-6 inhibitors in TG associated with anti-HLA DSAs. These data may fuel the hypothesis of different mechanisms underlying TGs (including the potentially different roles of natural killer cells) and suggest carefully selecting patients with TG for clinical trials or off-label treatment based on their antidonor serologic status.
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Affiliation(s)
- Alberto Mella
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonio Lavacca
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Diana Teodora Dodoi
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Roberto Presta
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Fabrizio Fop
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Marco Campagna
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Ana Maria Manzione
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Caterina Dolla
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Ester Gallo
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Isabella Abbasciano
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Chiara Gai
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Antonella Barreca
- Division of Pathology, “Città Della Salute e Della Scienza” Hospital, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Cristiana Caorsi
- Immunogenetic and Transplant Biology Center, “Città Della Salute e Della Scienza” Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Gloria Giovinazzo
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
| | - Luigi Biancone
- Renal Transplantation Center, “A. Vercellone,” Division of Nephrology Dialysis and Transplantation, Città Della Salute e Della Scienza Hospital and Department of Medical Sciences, University of Turin, Turin, Italy
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de Nattes T, Beadle J, Roufosse C. Biopsy-based transcriptomics in the diagnosis of kidney transplant rejection. Curr Opin Nephrol Hypertens 2024; 33:273-282. [PMID: 38411022 PMCID: PMC10990030 DOI: 10.1097/mnh.0000000000000974] [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] [Indexed: 02/28/2024]
Abstract
PURPOSE OF REVIEW The last year has seen considerable progress in translational research exploring the clinical utility of biopsy-based transcriptomics of kidney transplant biopsies to enhance the diagnosis of rejection. This review will summarize recent findings with a focus on different platforms, potential clinical applications, and barriers to clinical adoption. RECENT FINDINGS Recent literature has focussed on using biopsy-based transcriptomics to improve diagnosis of rejection, in particular antibody-mediated rejection. Different techniques of gene expression analysis (reverse transcriptase quantitative PCR, microarrays, probe-based techniques) have been used either on separate samples with ideally preserved RNA, or on left over tissue from routine biopsy processing. Despite remarkable consistency in overall patterns of gene expression, there is no consensus on acceptable indications, or whether biopsy-based transcriptomics adds significant value at reasonable cost to current diagnostic practice. SUMMARY Access to biopsy-based transcriptomics will widen as regulatory approvals for platforms and gene expression models develop. Clinicians need more evidence and guidance to inform decisions on how to use precious biopsy samples for biopsy-based transcriptomics, and how to integrate results with standard histology-based diagnosis.
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Affiliation(s)
- Tristan de Nattes
- Univ Rouen Normandie, INSERM U1234, CHU Rouen, Department of Nephrology, Rouen, France
| | - Jack Beadle
- Centre for Inflammatory Diseases, Department of Immunology and Inflammation, Imperial College London, London, UK
| | - Candice Roufosse
- Centre for Inflammatory Diseases, Department of Immunology and Inflammation, Imperial College London, London, UK
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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: 4] [Impact Index Per Article: 4.0] [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.
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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.
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Mengel M, Adam BA. Emerging phenotypes in kidney transplant rejection. Curr Opin Organ Transplant 2024; 29:97-103. [PMID: 38032262 DOI: 10.1097/mot.0000000000001130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2023]
Abstract
PURPOSE OF REVIEW This review focuses on more recently emerging rejection phenotypes in the context of time post transplantation and the resulting differential diagnostic challenges. It also discusses how novel ancillary diagnostic tools can potentially increase the accuracy of biopsy-based rejection diagnosis. RECENT FINDINGS With advances in reducing immunological risk at transplantation and improved immunosuppression treatment renal allograft survival improved. However, allograft rejection remains a major challenge and represent a frequent course for allograft failure. With prolonged allograft survival, novel phenotypes of rejection are emerging, which can show complex overlap and transition between cellular and antibody-mediated rejection mechanisms as well as mixtures of acute/active and chronic diseases. With the emerging complexity in rejection phenotypes, it is crucial to achieve diagnostic accuracy in the individual patient. SUMMARY The prospective validation and adoption of novel molecular and computational diagnostic tools into well defined and appropriate clinical context of uses will improve our ability to accurately diagnose, stage, and grade allograft rejection.
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Affiliation(s)
- Michael Mengel
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Alberta, Canada
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32
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Gauthier PT, Madill-Thomsen KS, Demko Z, Prewett A, Gauthier P, Halloran PF. Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release From Kidney Transplants in Different Disease States. Transplantation 2024; 108:898-910. [PMID: 38150492 PMCID: PMC10962427 DOI: 10.1097/tp.0000000000004877] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/05/2023] [Accepted: 10/23/2023] [Indexed: 12/29/2023]
Abstract
BACKGROUND Among all biopsies in the Trifecta-Kidney Study ( ClinicalTrials.gov NCT04239703), elevated plasma donor-derived cell-free DNA (dd-cfDNA) correlated most strongly with molecular antibody-mediated rejection (AMR) but was also elevated in other states: T cell-mediated rejection (TCMR), acute kidney injury (AKI), and some apparently normal biopsies. The present study aimed to define the molecular correlates of plasma dd-cfDNA within specific states. METHODS Dd-cfDNA was measured by the Prospera test. Molecular rejection and injury states were defined using the Molecular Microscope system. We studied the correlation between dd-cfDNA and the expression of genes, transcript sets, and classifier scores within specific disease states, and compared AMR, TCMR, and AKI to biopsies classified as normal and no injury (NRNI). RESULTS In all 604 biopsies, dd-cfDNA was elevated in AMR, TCMR, and AKI. Within AMR biopsies, dd-cfDNA correlated with AMR activity and stage. Within AKI, the correlations reflected acute parenchymal injury, including cell cycling. Within biopsies classified as MMDx Normal and archetypal No injury (NRNI), dd-cfDNA still correlated significantly with rejection- and injury-related genes. TCMR activity (eg, the TCMR Prob classifier) correlated with dd-cfDNA, but within TCMR biopsies, top gene correlations were complex and not the top TCMR-selective genes. CONCLUSIONS In kidney transplants, elevated plasma dd-cfDNA is associated with 3 distinct molecular states in the donor tissue: AMR, recent parenchymal injury (including cell cycling), and TCMR, potentially complicated by parenchymal disruption. Moreover, subtle rejection- and injury-related changes in the donor tissue can contribute to dd-cfDNA elevations in transplants considered to have no rejection or injury.
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Affiliation(s)
- Patrick T. Gauthier
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
- Transcriptome Sciences Inc, Edmonton, AB, Canada
| | - Katelynn S. Madill-Thomsen
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
- Transcriptome Sciences Inc, Edmonton, AB, Canada
| | | | | | | | - Philip F. Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
- Transcriptome Sciences Inc, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Park BH, Kim YN, Shin HS. New treatment for antibody-mediated rejection: interleukin-6 inhibitors. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:1-6. [PMID: 38725179 PMCID: PMC11075910 DOI: 10.4285/ctr.23.0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 02/15/2024] [Accepted: 03/01/2024] [Indexed: 05/14/2024]
Abstract
Following kidney transplantation, antibody-mediated rejection (AMR) occurs when the antibodies of the immune system attack the transplanted organ, leading to damage of the kidney tissue. De novo human leukocyte antigen donor-specific antibodies (HLA-DSAs) play a key role in AMR. Current therapeutic approaches include intravenous immunoglobulin, anti-CD20 antibodies, and plasmapheresis. In cases resistant to treatment, proteasome inhibitors and C5 inhibitors may be employed. Nevertheless, a pressing need exists for new medications to improve transplant survival and reduce complications. In the context of AMR, interleukin (IL)-6 is instrumental in the development and maturation of B cells into plasma cells, which then produce HLA-DSAs targeting the allograft. IL-6 inhibitors are currently under investigation and show promise due to the essential role of IL-6 in the immune response; however, additional research is necessary.
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Affiliation(s)
- Byung Hwa Park
- Division of Nephrology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Ye Na Kim
- Division of Nephrology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
| | - Ho Sik Shin
- Division of Nephrology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
- Transplantation Research Institute, Kosin University College of Medicine, Busan, Korea
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Naesens M, Roufosse C, Haas M, Lefaucheur C, Mannon RB, Adam BA, Aubert O, Böhmig GA, Callemeyn J, Clahsen-van Groningen M, Cornell LD, Demetris AJ, Drachenberg CB, Einecke G, Fogo AB, Gibson IW, Halloran P, Hidalgo LG, Horsfield C, Huang E, Kikić Ž, Kozakowski N, Nankivell B, Rabant M, Randhawa P, Riella LV, Sapir-Pichhadze R, Schinstock C, Solez K, Tambur AR, Thaunat O, Wiebe C, Zielinski D, Colvin R, Loupy A, Mengel M. The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics. Am J Transplant 2024; 24:338-349. [PMID: 38032300 DOI: 10.1016/j.ajt.2023.10.016] [Citation(s) in RCA: 79] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 10/04/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023]
Abstract
The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.
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Affiliation(s)
- Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
| | - Candice Roufosse
- Department of Immunology and Inflammation, Faculty Medicine, Imperial College London, London, UK.
| | - Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Carmen Lefaucheur
- Université Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, France & Department of Nephrology and Transplantation, Saint-Louis Hospital, Paris, France
| | | | - Benjamin A Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Olivier Aubert
- Université Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, France & Department of Transplantation, Necker Hospital, Paris, France
| | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Jasper Callemeyn
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Marian Clahsen-van Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus University Center Rotterdam, Rotterdam, The Netherlands, Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany
| | - Lynn D Cornell
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Anthony J Demetris
- UPMC Hepatic and Transplantation Pathology, Pittsburgh, Pennsylvania, USA
| | | | - Gunilla Einecke
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany
| | - Agnes B Fogo
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Ian W Gibson
- Department of Pathology, University of Manitoba, Winnipeg, Canada
| | - Philip Halloran
- Department of Medicine, Alberta Transplant Applied Genomics Centre, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada
| | - Luis G Hidalgo
- Department of Surgery, University of Wisconsin, Madison, Wisconsin, USA
| | | | - Edmund Huang
- Department of Medicine, Division of Nephrology, Cedars-Sinai Medical Center, West Hollywood, California, USA
| | - Željko Kikić
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | | | - Brian Nankivell
- Department of Renal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Marion Rabant
- Pathology department, Necker-Enfants Malades Hospital, Paris, France
| | - Parmjeet Randhawa
- Department of Pathology, Thomas E. Starzl Transplant Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Leonardo V Riella
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ruth Sapir-Pichhadze
- Division of Nephrology & Multi-Organ Transplant Program, McGill University, Montreal, Quebec, Canada
| | - Carrie Schinstock
- Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Kim Solez
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Anat R Tambur
- Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA
| | - Olivier Thaunat
- Department of Transplantation Nephrology and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Chris Wiebe
- Department of Medicine and Department of Immunology, University of Manitoba, Winnipeg, Canada
| | - Dina Zielinski
- Université Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, France & Department of Transplantation, Necker Hospital, Paris, France
| | - Robert Colvin
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Alexandre Loupy
- Université Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, France & Department of Transplantation, Necker Hospital, Paris, France
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
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Sikosana ML, Reeve J, Madill-Thomsen KS, Halloran PF. Using Regression Equations to Enhance Interpretation of Histology Lesions of Kidney Transplant Rejection. Transplantation 2024; 108:445-454. [PMID: 37726883 PMCID: PMC10798587 DOI: 10.1097/tp.0000000000004783] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/13/2023] [Accepted: 07/07/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND The Banff system for histologic diagnosis of rejection in kidney transplant biopsies uses guidelines to assess designated features-lesions, donor-specific antibody (DSA), and C4d staining. We explored whether using regression equations to interpret the features as well as current guidelines could establish the relative importance of each feature and improve histologic interpretation. METHODS We developed logistic regression equations using the designated features to predict antibody-mediated rejection (AMR/mixed) and T-cell-mediated rejection (TCMR/mixed) in 1679 indication biopsies from the INTERCOMEX study ( ClinicalTrials.gov NCT01299168). Equations were trained on molecular diagnoses independent of the designated features. RESULTS In regression and random forests, the important features predicting molecular rejection were as follows: for AMR, ptc and g, followed by cg; for TCMR, t > i. V-lesions were relatively unimportant. C4d and DSA were also relatively unimportant for predicting AMR: by AUC, the model excluding them (0.853) was nearly as good as the model including them (0.860). Including time posttransplant slightly but significantly improved all models. By AUC, regression predicted molecular AMR and TCMR better than Banff histologic diagnoses. More importantly, in biopsies called "no rejection" by Banff guidelines, regression equations based on histology features identified histologic and molecular rejection-related changes in some biopsies and improved survival predictions. Thus, regression can screen for missed rejection. CONCLUSIONS Using lesion-based regression equations in addition to Banff histology guidelines defines the relative important of histology features for identifying rejection, allows screening for potential missed diagnoses, and permits early estimates of AMR when C4d and DSA are not available.
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Affiliation(s)
- Majid L.N. Sikosana
- Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Jeff Reeve
- Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada
| | | | - Philip F. Halloran
- Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
- Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada
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Leckie-Harre A, Silverman I, Wu H, Humphreys BD, Malone AF. Sequencing of Physically Interacting Cells in Human Kidney Allograft Rejection to Infer Contact-dependent Immune Cell Transcription. Transplantation 2024; 108:421-429. [PMID: 37638864 PMCID: PMC10798591 DOI: 10.1097/tp.0000000000004762] [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: 04/06/2023] [Revised: 06/05/2023] [Accepted: 06/25/2023] [Indexed: 08/29/2023]
Abstract
BACKGROUND Rejection requires cell-cell contact involving immune cells. Inferring the transcriptional programs of cell-cell interactions from single-cell RNA-sequencing (scRNA-seq) data is challenging as spatial information is lost. METHODS We combined a CD45 pos enrichment strategy with Cellular Indexing of Transcriptomes and Epitopes by sequencing based quantification of leukocyte surface proteins to analyze cell-cell interactions in 11 human kidney transplant biopsies encompassing a spectrum of rejection diagnoses. scRNA-seq was performed using the 10X Genomics platform. We applied the sequencing physically interacting cells computational method to deconvolute the transcriptional profiles of heterotypic physically interacting cells. RESULTS The 11 human allograft biopsies generated 31 203 high-quality single-cell libraries. Clustering was further refined by combining Cellular Indexing of Transcriptomes and Epitopes by sequencing data from 6 different leukocyte-specific surface proteins. Three of 6 doublet clusters were identified as physically interacting cell complexes; macrophages or dendritic cells bound to B cells or plasma cells; natural killer (NK) or T cells bound to macrophages or dendritic cells and NK or T cells bound to endothelial cells. Myeloid-lymphocyte physically interacting cell complexes expressed activated and proinflammatory genes. Lymphocytes physically interacting with endothelial cells were enriched for NK and CD4 T cells. NK cell-endothelial cell contact caused increased expression of endothelial proinflammatory genes CXCL9 and CXCL10 and NK cell proinflammatory genes CCL3 , CCL4 , and GNLY . CONCLUSIONS The transcriptional profiles of physically interacting cells from human kidney transplant biopsies can be inferred from scRNA-seq data using the sequencing physically interacting cells method. This approach complements previous methods that estimate cell-cell physical contact from scRNA-seq data.
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Affiliation(s)
- Aidan Leckie-Harre
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - Isabel Silverman
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - Haojia Wu
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - Benjamin D. Humphreys
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO
- Department of Developmental Biology, Washington University in St. Louis School of Medicine, St. Louis, MO
| | - Andrew F. Malone
- Division of Nephrology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO
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Gauthier PT, Mackova M, Hirji A, Weinkauf J, Timofte IL, Snell GI, Westall GP, Havlin J, Lischke R, Zajacová A, Simonek J, Hachem R, Kreisel D, Levine D, Kubisa B, Piotrowska M, Juvet S, Keshavjee S, Jaksch P, Klepetko W, Halloran K, Halloran PF. Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies. Am J Transplant 2023; 23:1922-1938. [PMID: 37295720 DOI: 10.1016/j.ajt.2023.06.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 05/29/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.
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Affiliation(s)
| | | | - Alim Hirji
- University of Alberta, Edmonton, Alberta, Canada
| | | | | | - Greg I Snell
- Alfred Hospital Lung Transplant Service, Melbourne, Victoria, Australia
| | - Glen P Westall
- Alfred Hospital Lung Transplant Service, Melbourne, Victoria, Australia
| | - Jan Havlin
- University Hospital Motol, Prague, Czech Republic
| | | | | | - Jan Simonek
- University Hospital Motol, Prague, Czech Republic
| | - Ramsey Hachem
- Washington University in St Louis, St. Louis, Missouri, USA
| | - Daniel Kreisel
- Washington University in St Louis, St. Louis, Missouri, USA
| | | | - Bartosz Kubisa
- Pomeranian Medical University of Szczecin, Szczecin, Poland
| | | | - Stephen Juvet
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Shaf Keshavjee
- Toronto Lung Transplant Program, University Health Network, Toronto, Ontario, Canada
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38
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Rosales IA, Smith RN, Colvin RB. Histologic and molecular features of antibody-mediated rejection. Curr Opin Organ Transplant 2023; 28:340-344. [PMID: 37526088 DOI: 10.1097/mot.0000000000001088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
PURPOSE OF REVIEW This review aims to summarize the highlights from recent research that involved pathological and molecular analysis of kidney allografts. RECENT FINDINGS As the research on antibody-mediated rejection (AMR) continues to evolve, studies are focused on identification through transcript studies of pathogenetic pathways involved in the development of AMR as well as refinement of diagnostic methods either by correlating Banff pathologic lesions with clinical and molecular data or by machine learning. Of note, the past year has generated high impact research that underscore the importance of pathologic and molecular correlations and detection of transcripts or gene sets that would aid prognostication. The studies involving refinement of pathologic criteria also highlight the continuous efforts to achieve diagnostic accuracy and standardization. SUMMARY Research involving histologic and molecular characteristics that define AMR are central to identification and understanding of pathogenetic pathways and remain critical in the development of diagnostic criteria.
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Affiliation(s)
- Ivy A Rosales
- Immunopathology Research Laboratory, Department of Pathology
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rex Neal Smith
- Immunopathology Research Laboratory, Department of Pathology
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Robert B Colvin
- Immunopathology Research Laboratory, Department of Pathology
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
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39
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Ruan DF, Fribourg M, Yuki Y, Park YH, Martin M, Kelly G, Lee B, Miguel de Real R, Lee R, Geanon D, Kim-Schulze S, McCarthy M, Chun N, Cravedi P, Carrington M, Heeger PS, Horowitz A. Understanding the heterogeneity of alloreactive natural killer cell function in kidney transplantation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.01.555962. [PMID: 37732256 PMCID: PMC10508724 DOI: 10.1101/2023.09.01.555962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/22/2023]
Abstract
Human Natural Killer (NK) cells are heterogeneous lymphocytes regulated by variegated arrays of germline-encoded activating and inhibitory receptors. They acquire the ability to detect polymorphic self-antigen via NKG2A/HLA-E or KIR/HLA-I ligand interactions through an education process. Correlations among HLA/KIR genes, kidney transplantation pathology and outcomes suggest that NK cells participate in allograft injury, but mechanisms linking NK HLA/KIR education to antibody-independent pathological functions remain unclear. We used CyTOF to characterize pre- and post-transplant peripheral blood NK cell phenotypes/functions before and after stimulation with allogeneic donor cells. Unsupervised clustering identified unique NK cell subpopulations present in varying proportions across patients, each of which responded heterogeneously to donor cells based on donor ligand expression patterns. Analyses of pre-transplant blood showed that educated, NKG2A/KIR-expressing NK cells responded greater than non-educated subsets to donor stimulators, and this heightened alloreactivity persisted > 6 months post-transplant despite immunosuppression. In distinct test and validation sets of patients participating in two clinical trials, pre-transplant donor-induced release of NK cell Ksp37, a cytotoxicity mediator, correlated with 2-year and 5-year eGFR. The findings explain previously reported associations between NK cell genotypes and transplant outcomes and suggest that pre-transplant NK cell analysis could function as a risk-assessment biomarker for transplant outcomes.
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Affiliation(s)
- Dan Fu Ruan
- Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Miguel Fribourg
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yuko Yuki
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute Frederick, MD, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Yeon-Hwa Park
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute Frederick, MD, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Maureen Martin
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute Frederick, MD, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Geoffrey Kelly
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Brian Lee
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ronaldo Miguel de Real
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Rachel Lee
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Geanon
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Seunghee Kim-Schulze
- Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Melissa McCarthy
- Dean’s Flow Cytometry CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nicholas Chun
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Paolo Cravedi
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Mary Carrington
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute Frederick, MD, USA
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Peter S. Heeger
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
- These authors contributed equally
| | - Amir Horowitz
- Department of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- The Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- These authors contributed equally
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Beadle J, Papadaki A, Toulza F, Santos E, Willicombe M, McLean A, Peters J, Roufosse C. Application of the Banff Human Organ Transplant Panel to kidney transplant biopsies with features suspicious for antibody-mediated rejection. Kidney Int 2023; 104:526-541. [PMID: 37172690 DOI: 10.1016/j.kint.2023.04.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 03/07/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023]
Abstract
The Banff Classification for Allograft Pathology includes the use of gene expression in the diagnosis of antibody-mediated rejection (AMR) of kidney transplants, but a predictive set of genes for classifying biopsies with 'incomplete' phenotypes has not yet been studied. Here, we developed and assessed a gene score that, when applied to biopsies with features of AMR, would identify cases with a higher risk of allograft loss. To do this, RNA was extracted from a continuous retrospective cohort of 349 biopsies randomized 2:1 to include 220 biopsies in a discovery cohort and 129 biopsies in a validation cohort. The biopsies were divided into three groups: 31 that fulfilled the 2019 Banff Criteria for active AMR, 50 with histological features of AMR but not meeting the full criteria (Suspicious-AMR), and 269 with no features of active AMR (No-AMR). Gene expression analysis using the 770 gene Banff Human Organ Transplant NanoString panel was carried out with LASSO Regression performed to identify a parsimonious set of genes predictive of AMR. We identified a nine gene score that was highly predictive of active AMR (accuracy 0.92 in the validation cohort) and was strongly correlated with histological features of AMR. In biopsies suspicious for AMR, our gene score was strongly associated with risk of allograft loss and independently associated with allograft loss in multivariable analysis. Thus, we show that a gene expression signature in kidney allograft biopsy samples can help classify biopsies with incomplete AMR phenotypes into groups that correlate strongly with histological features and outcomes.
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Affiliation(s)
- Jack Beadle
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK; Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK.
| | - Artemis Papadaki
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK
| | - Frederic Toulza
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK
| | - Eva Santos
- H&I Laboratory, North West London Pathology, London, UK
| | - Michelle Willicombe
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK; Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK
| | - Adam McLean
- Imperial College Renal and Transplant Centre, Imperial College NHS Trust, London, UK
| | - James Peters
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK
| | - Candice Roufosse
- Centre for Inflammatory Disease, Department of Immunology and Inflammation, Faculty of Medicine, Imperial College London, London, UK; Department of Cellular Pathology, North West London Pathology, London, UK
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41
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Sarwal MM, Naesens M. Urine trumps the protocol biopsy for subclinical rejection surveillance. Kidney Int 2023; 104:432-439. [PMID: 37599018 DOI: 10.1016/j.kint.2023.06.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/09/2023] [Accepted: 06/15/2023] [Indexed: 08/22/2023]
Affiliation(s)
- Minnie M Sarwal
- Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, California, USA.
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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Sasaki H, Tanabe T, Tsuji T, Hotta K. Mechanism and treatment for chronic antibody-mediated rejection in kidney transplant recipients. Int J Urol 2023; 30:624-633. [PMID: 37306194 DOI: 10.1111/iju.15197] [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: 02/12/2023] [Accepted: 04/11/2023] [Indexed: 06/13/2023]
Abstract
Chronic antibody-mediated rejection of kidney transplantation is a major cause of late-stage graft loss. Donor-specific antibodies are the main cause of antibody-mediated rejection; in particular, de novo donor-specific antibodies are a risk factor for chronic active antibody-mediated rejection. The level of de novo donor-specific antibodies tends to increase with time throughout long-term graft survival. Donor-specific antibodies induce humoral rejection through complement activation, which results in tissue injury and coagulation. Additionally, complement activation promotes the migration of inflammatory cells through the innate immune response, causing endothelial injury. This inflammatory response may cause persistent glomerulitis and peritubular capillaritis, leading to fixed pathological lesions that impair graft function. No treatment has been established for chronic antibody-mediated rejection, a condition in which antibody-mediated rejection becomes irreversible. Thus, antibody-mediated rejection must be detected and treated while it is still reversible. In this review, we discuss the development of de novo donor-specific antibodies and the mechanisms leading to chronic antibody-mediated rejection and summarize the current treatment options and the latest biomarkers for detecting chronic antibody-mediated rejection at an earlier stage.
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Affiliation(s)
- Hajime Sasaki
- Division of Renal Surgery and Transplantation, Department of Urology, Jichi Medical University Hospital, Shimotsuke, Japan
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan
| | - Tatsu Tanabe
- Department of Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan
| | - Takahiro Tsuji
- Department of Pathology, Sapporo City General Hospital, Sapporo, Japan
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
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43
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Betjes MGH, De Weerd A. Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots. Front Med (Lausanne) 2023; 10:1215167. [PMID: 37502354 PMCID: PMC10368955 DOI: 10.3389/fmed.2023.1215167] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/09/2023] [Indexed: 07/29/2023] Open
Abstract
The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.
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Madill-Thomsen KS, Böhmig GA, Bromberg J, Einecke G, Eskandary F, Gupta G, Myslak M, Viklicky O, Perkowska-Ptasinska A, Solez K, Halloran PF. Relating Molecular T Cell-mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis. Transplantation 2023; 107:1102-1114. [PMID: 36575574 PMCID: PMC10125115 DOI: 10.1097/tp.0000000000004396] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/29/2022] [Accepted: 09/12/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND We studied the variation in molecular T cell-mediated rejection (TCMR) activity in kidney transplant indication biopsies and its relationship with histologic lesions (particularly tubulitis and atrophy-fibrosis) and time posttransplant. METHODS We examined 175 kidney transplant biopsies with molecular TCMR as defined by archetypal analysis in the INTERCOMEX study ( ClinicalTrials.gov #NCT01299168). TCMR activity was defined by a molecular classifier. RESULTS Archetypal analysis identified 2 TCMR classes, TCMR1 and TCMR2: TCMR1 had higher TCMR activity and more antibody-mediated rejection ("mixed") activity and arteritis but little hyalinosis, whereas TCMR2 had less TCMR activity but more atrophy-fibrosis. TCMR1 and TCMR2 had similar levels of molecular injury and tubulitis. Both TCMR1 and TCMR2 biopsies were uncommon after 2 y posttransplant and were rare after 10 y, particularly TCMR1. Within late TCMR biopsies, TCMR classifier activity and activity molecules such as IFNG fell progressively with time, but tubulitis and molecular injury were sustained. Atrophy-fibrosis was increased in TCMR biopsies, even in the first year posttransplant, and rose with time posttransplant. TCMR1 and TCMR2 both reduced graft survival, but in random forests, the strongest determinant of survival after biopsies with TCMR was molecular injury, not TCMR activity. CONCLUSIONS TCMR varies in intensity but is always strongly related to molecular injury and atrophy-fibrosis, which ultimately explains its effect on survival. We hypothesize, based on the reciprocal relationship with hyalinosis, that the TCMR1-TCMR2 gradient reflects calcineurin inhibitor drug underexposure, whereas the time-dependent decline in TCMR activity and frequency after the first year reflects T-cell exhaustion.
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Affiliation(s)
| | - Georg A. Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Gunilla Einecke
- Department of Nephrology, Hannover Medical School, Hannover, Germany
| | - Farsad Eskandary
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Marek Myslak
- Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation SPWSZ Hospital, Pomeranian Medical University, Szczecin, Poland
| | - Ondrej Viklicky
- Department of Nephrology and Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | | | - Kim Solez
- Department of Laboratory Medicine and Pathology, Division of Anatomical Pathology, University of Alberta, Edmonton, Canada
| | - Philip F. Halloran
- Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada
- Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Böhmig GA, Halloran PF, Feucht HE. On a Long and Winding Road: Alloantibodies in Organ Transplantation. Transplantation 2023; 107:1027-1041. [PMID: 36944603 DOI: 10.1097/tp.0000000000004550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
Today we know that both the humoral and the cellular arm of the immune system are engaged in severe immunological challenges. A close interaction between B and T cells can be observed in most "natural" challenges, including infections, malignancies, and autoimmune diseases. The importance and power of humoral immunity are impressively demonstrated by the current coronavirus disease 2019 pandemic. Organ transplant rejection is a normal immune response to a completely "artificial" challenge. It took a long time before the multifaceted action of different immunological forces was recognized and a unified, generally accepted opinion could be formed. Here, we address prominent paradigms and paradigm shifts in the field of transplantation immunology. We identify several instances in which the transplant community missed a timely paradigm shift because essential, available knowledge was ignored. Moreover, we discuss key findings that critically contributed to our understanding of transplant immunology but sometimes developed with delay and in a roundabout way, as was the case with antibody-mediated rejection-a main focus of this article. These include the discovery of the molecular principles of histocompatibility, the recognition of the microcirculation as a key interface of immune damage, the refinement of alloantibody detection, the description of C4d as a footmark of endothelium-bound antibody, and last but not least, the developments in biopsy-based diagnostics beyond conventional morphology, which only now give us a glimpse of the enormous complexity and pathogenetic diversity of rejection.
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Affiliation(s)
- Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Philip F Halloran
- Alberta Transplant Applied Genomics Centre, ATAGC, University of Alberta, Edmonton, AB, Canada
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Halloran PF, Reeve J, Madill-Thomsen KS, Demko Z, Prewett A, Gauthier P, Billings P, Lawrence C, Lowe D, Hidalgo LG. Antibody-mediated Rejection Without Detectable Donor-specific Antibody Releases Donor-derived Cell-free DNA: Results From the Trifecta Study. Transplantation 2023; 107:709-719. [PMID: 36190186 PMCID: PMC9946174 DOI: 10.1097/tp.0000000000004324] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/08/2022] [Accepted: 07/12/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND Trifecta (ClinicalTrials.gov #NCT04239703) is a prospective trial defining relationships between donor-derived cell-free DNA (dd-cfDNA), donor-specific antibody (DSA), and molecular findings in kidney transplant biopsies. Previous analyses of double results showed dd-cfDNA was strongly associated with rejection-associated molecules in the biopsy. The present study analyzed the triple results in 280 biopsies, focusing on the question of dd-cfDNA levels in DSA-negative antibody-mediated rejection (AMR). METHODS Molecular Microscope Diagnostic System biopsy testing was performed at Alberta Transplant Applied Genomics Centre, dd-cfDNA testing at Natera, Inc, and central HLA antibody testing at One Lambda Inc. Local DSA and histologic diagnoses were assigned per center standard-of-care. RESULTS DSA was frequently negative in both molecular (56%) and histologic (51%) AMR. DSA-negative AMR had slightly less molecular AMR activity and histologic peritubular capillaritis than DSA-positive AMR. However, all AMRs-DSA-positive or -negative-showed elevated %dd-cfDNA. There was no association between dd-cfDNA and DSA in biopsies without rejection. In AMR, %dd-cfDNA ≥1.0 was more frequent (75%) than DSA positivity (44%). In logistic regression, dd-cfDNA percent (area under the curve [AUC] 0.85) or quantity (AUC 0.86) predicted molecular AMR better than DSA (AUC 0.66). However, the best predictions incorporated both dd-cfDNA and DSA, plus time posttransplant (AUC 0.88). CONCLUSIONS DSA-negative AMR has moderately decreased mean molecular and histologic AMR-associated features compared with DSA-positive AMR, though similarly elevated dd-cfDNA levels. In predicting AMR at the time of indication biopsies in this population, dd-cfDNA is superior to DSA, reflecting the prevalence of DSA-negative AMR, but the optimal predictions incorporated both dd-cfDNA and DSA.
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Affiliation(s)
- Philip F. Halloran
- Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, AB, Canada
- Transcriptome Sciences, Inc, Edmonton, AB, Canada
| | - Jeff Reeve
- Alberta Transplant Applied Genomics Center, University of Alberta, Edmonton, AB, Canada
| | | | | | | | | | | | | | | | - Luis G. Hidalgo
- Division of Transplantation, Department of Surgery, University of Wisconsin, Madison, WI
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47
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Llinàs-Mallol L, Raïch-Regué D, Pascual J, Crespo M. Alloimmune risk assessment for antibody-mediated rejection in kidney transplantation: A practical proposal. Transplant Rev (Orlando) 2023; 37:100745. [PMID: 36572001 DOI: 10.1016/j.trre.2022.100745] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 12/07/2022] [Accepted: 12/11/2022] [Indexed: 12/24/2022]
Abstract
Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Although an improvement in graft survival has been observed in the last decades with the use of different immunosuppressive drugs, this is still limited in time with antibody-mediated rejection being a main cause of graft-loss. Immune monitoring and risk assessment of antibody-mediated rejection before and after kidney transplantation with useful biomarkers is key to tailoring treatments to achieve the best outcomes. Here, we provide a review of the rationale and several accessible tools for immune monitoring, from the most classic to the modern ones. Finally, we end up discussing a practical proposal for alloimmune risk assessment in kidney transplantation, including histocompatibility leukocyte antigen (HLA) and non-HLA antibodies, HLA molecular mismatch analysis and characterization of peripheral blood immune cells.
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Affiliation(s)
- Laura Llinàs-Mallol
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Dàlia Raïch-Regué
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Julio Pascual
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain.
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain.
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Khairallah P, Robbins-Juarez S, Patel S, Shah V, Toma K, Fernandez H, Dube GK, King K, Mohan S, Husain SA, Morris H, Crew RJ. Tocilizumab for the treatment of chronic antibody mediated rejection in kidney transplant recipients. Clin Transplant 2023; 37:e14853. [PMID: 36398915 DOI: 10.1111/ctr.14853] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 09/28/2022] [Accepted: 11/04/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Chronic active antibody-mediated rejection (CAAMR) constitutes a dominant form of late allograft failure. Several treatment strategies directed at CAAMR have been attempted but proven ineffective at delaying kidney function decline or reducing donor-specific antibodies (DSA). We describe our single-center experience using tocilizumab in patients with CAAMR. METHODS This is a retrospective analysis using electronic medical records. 38 kidney transplant recipients at Columbia University Irving Medical Center who had been prescribed tocilizumab and followed for at least 3 months between August 2013 through December 2019 were included. RESULTS Tocilizumab use was associated with a decrease in the rate of estimated glomerular filtration rate (eGFR) decline in the 6 months following treatment initiation as compared to the 3 months before tocilizumab was initiated (difference between slopes before and after initiation of treatment = 2.6 mL/min/1.73 m2 (SE = .8, p = .002) per month for up to 6 months following Tocilizumab initiation). Allograft biopsies showed significant improvement in interstitial inflammation scores (score 1(0,1) to 0 (0,1), p = .03) while other histologic scores remained stable. There was no significant change in proteinuria or DSA titers post-treatment with tocilizumab. CONCLUSIONS Treatment of CAAMR with tocilizumab was associated with a decrease in the rate of eGFR decline and a reduction in interstitial inflammation scores in patients with CAAMR.
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Affiliation(s)
| | - Shelief Robbins-Juarez
- Department of Internal Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Shefali Patel
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Vaqar Shah
- Department of Medicine, SUNY University at Buffalo, Buffalo, New York, USA
| | - Katherine Toma
- Jersey Coast Nephrology and Hypertension Associates, Brick, New Jersey, USA
| | - Hilda Fernandez
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Geoffrey K Dube
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Kristen King
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Sumit Mohan
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Syed Ali Husain
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Heather Morris
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
| | - Russell John Crew
- Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA
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49
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The Molecular Microscope Diagnostic System: Assessment of Rejection and Injury in Heart Transplant Biopsies. Transplantation 2023; 107:27-44. [PMID: 36508644 DOI: 10.1097/tp.0000000000004323] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
This review describes the development of the Molecular Microscope Diagnostic System (MMDx) for heart transplant endomyocardial biopsies (EMBs). MMDx-Heart uses microarrays to measure biopsy-based gene expression and ensembles of machine learning algorithms to interpret the results and compare each new biopsy to a large reference set of earlier biopsies. MMDx assesses T cell-mediated rejection (TCMR), antibody-mediated rejection (AMR), recent parenchymal injury, and atrophy-fibrosis, continually "learning" from new biopsies. Rejection-associated transcripts mapped in kidney transplants and experimental systems were used to identify TCMR, AMR, and recent injury-induced inflammation. Rejection and injury emerged as gradients of intensity, rather than binary classes. AMR was one-third donor-specific antibody (DSA)-negative, and many EMBs first considered to have no rejection displayed minor AMR-like changes, with increased probability of DSA positivity and subtle inflammation. Rejection-associated transcript-based algorithms now classify EMBs as "Normal," "Minor AMR changes," "AMR," "possible AMR," "TCMR," "possible TCMR," and "recent injury." Additionally, MMDx uses injury-associated transcript sets to assess the degree of parenchymal injury and atrophy-fibrosis in every biopsy and study the effect of rejection on the parenchyma. TCMR directly injures the parenchyma whereas AMR usually induces microcirculation stress but relatively little initial parenchymal damage, although slowly inducing parenchymal atrophy-fibrosis. Function (left ventricular ejection fraction) and short-term risk of failure are strongly determined by parenchymal injury. These discoveries can guide molecular diagnostic applications, either as a central MMDx system or adapted to other platforms. MMDx can also help calibrate noninvasive blood-based biomarkers to avoid unnecessary biopsies and monitor response to therapy.
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Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: A Sensitization in Transplantation: Assessment of Risk consensus document. Am J Transplant 2023; 23:115-132. [PMID: 36695614 DOI: 10.1016/j.ajt.2022.11.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/29/2022] [Accepted: 11/04/2022] [Indexed: 01/13/2023]
Abstract
Although anti-HLA (Human Leukocyte Antigen) donor-specific antibodies (DSAs) are commonly measured in clinical practice and their relationship with transplant outcome is well established, clinical recommendations for anti-HLA antibody assessment are sparse. Supported by a careful and critical review of the current literature performed by the Sensitization in Transplantation: Assessment of Risk 2022 working group, this consensus report provides clinical practice recommendations in kidney, heart, lung, and liver transplantation based on expert assessment of quality and strength of evidence. The recommendations address 3 major clinical problems in transplantation and include guidance regarding posttransplant DSA assessment and application to diagnostics, prognostics, and therapeutics: (1) the clinical implications of positive posttransplant DSA detection according to DSA status (ie, preformed or de novo), (2) the relevance of posttransplant DSA assessment for precision diagnosis of antibody-mediated rejection and for treatment management, and (3) the relevance of posttransplant DSA for allograft prognosis and risk stratification. This consensus report also highlights gaps in current knowledge and provides directions for clinical investigations and trials in the future that will further refine the clinical utility of posttransplant DSA assessment, leading to improved transplant management and patient care.
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