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1
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Delsante M, Gandolfini I, Palmisano A, Benigno GD, Gentile M, Rossi GM, Fiaccadori E, Maggiore U. Early and late antibody mediated rejection: Which game is the complement playing? Transplant Rev (Orlando) 2025; 39:100889. [PMID: 39591699 DOI: 10.1016/j.trre.2024.100889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/05/2024] [Accepted: 11/18/2024] [Indexed: 11/28/2024]
Abstract
The role of the complement system in antibody mediated rejection (AMR) emerged in the last decades, and the demonstration of the presence of complement fragments in renal allograft biopsies is a consolidated diagnostic sign of AMR. However, antibodies against donor antigens may lead to microvascular inflammation and endothelial injury even in the absence of complement activation, and growing evidence suggests that complement-independent mechanisms may be prominent in late (i.e., occurring >6 months after transplantation) vs early AMR. Different donor specific antibodies (DSA) with different biological features and complement activation ability may be involved in late or early AMR. Downregulation of tissue complement inhibitors may happen early after transplantation, partially due to ischemia reperfusion injury, and could facilitate complement activation in early vs late AMR. Clinical and histological features of late AMR and C4d negative AMR seem to converge, and this narrative review analyzes the evidence that supports lower complement activation in late vs early AMR, including differential C4d staining prevalence based on the time after transplantation, differential response to anti-complement therapy and other direct and indirect signs of the complement system activation. The therapeutic approach in early vs late AMR should take into account possible differences in the pathophysiological mechanisms of microvascular inflammation and endothelial injury in early vs late AMR.
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Affiliation(s)
- Marco Delsante
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy.
| | - Ilaria Gandolfini
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Alessandra Palmisano
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Giuseppe Daniele Benigno
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Micaela Gentile
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Giovanni Maria Rossi
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Enrico Fiaccadori
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Umberto Maggiore
- Nephrology Unit, Parma University Hospital, & Department of Medicine and Surgery, University of Parma, Parma, Italy
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2
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Maddur H, Wilson N, Patil P, Asrani S. Rejection in Liver Transplantation Recipients. J Clin Exp Hepatol 2024; 14:101363. [PMID: 38495462 PMCID: PMC10943490 DOI: 10.1016/j.jceh.2024.101363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.
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3
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Kardol-Hoefnagel T, Senejohnny DM, Kamburova EG, Wisse BW, Reteig L, Gruijters ML, Joosten I, Allebes WA, van der Meer A, Hilbrands LB, Baas MC, Spierings E, Hack CE, van Reekum FE, van Zuilen AD, Verhaar MC, Bots ML, Drop ACAD, Plaisier L, Melchers RCA, Seelen MAJ, Sanders JS, Hepkema BG, Lambeck AJA, Bungener LB, Roozendaal C, Tilanus MGJ, Voorter CE, Wieten L, van Duijnhoven EM, Gelens MACJ, Christiaans MHL, van Ittersum FJ, Nurmohamed SA, Lardy NM, Swelsen W, van der Pant KAMI, van der Weerd NC, Ten Berge IJM, Hoitsma A, van der Boog PJM, de Fijter JW, Betjes MGH, Roelen DL, Claas FH, Bemelman FJ, Senev A, Naesens M, Heidt S, Otten HG. Determination of the clinical relevance of donor epitope-specific HLA-antibodies in kidney transplantation. HLA 2024; 103:e15346. [PMID: 38239046 DOI: 10.1111/tan.15346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 12/15/2023] [Accepted: 01/02/2024] [Indexed: 01/23/2024]
Abstract
In kidney transplantation, survival rates are still partly impaired due to the deleterious effects of donor specific HLA antibodies (DSA). However, not all luminex-defined DSA appear to be clinically relevant. Further analysis of DSA recognizing polymorphic amino acid configurations, called eplets or functional epitopes, might improve the discrimination between clinically relevant vs. irrelevant HLA antibodies. To evaluate which donor epitope-specific HLA antibodies (DESAs) are clinically important in kidney graft survival, relevant and irrelevant DESAs were discerned in a Dutch cohort of 4690 patients using Kaplan-Meier analysis and tested in a cox proportional hazard (CPH) model including nonimmunological variables. Pre-transplant DESAs were detected in 439 patients (9.4%). The presence of certain clinically relevant DESAs was significantly associated with increased risk on graft loss in deceased donor transplantations (p < 0.0001). The antibodies recognized six epitopes of HLA Class I, 3 of HLA-DR, and 1 of HLA-DQ, and most antibodies were directed to HLA-B (47%). Fifty-three patients (69.7%) had DESA against one donor epitope (range 1-5). Long-term graft survival rate in patients with clinically relevant DESA was 32%, rendering DESA a superior parameter to classical DSA (60%). In the CPH model, the hazard ratio (95% CI) of clinically relevant DESAs was 2.45 (1.84-3.25) in deceased donation, and 2.22 (1.25-3.95) in living donation. In conclusion, the developed model shows the deleterious effect of clinically relevant DESAs on graft outcome which outperformed traditional DSA-based risk analysis on antigen level.
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Affiliation(s)
- Tineke Kardol-Hoefnagel
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Elena G Kamburova
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Bram W Wisse
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Leon Reteig
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Maartje L Gruijters
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Irma Joosten
- Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wil A Allebes
- Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Arnold van der Meer
- Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Luuk B Hilbrands
- Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Marije C Baas
- Department of Nephrology, Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Eric Spierings
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Central Diagnostic Laboratory (CDL), University Medical Center Utrecht, Utrecht, The Netherlands
| | - Cornelis E Hack
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Franka E van Reekum
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Arjan D van Zuilen
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Michiel L Bots
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Adriaan C A D Drop
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Loes Plaisier
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Rowena C A Melchers
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Marc A J Seelen
- Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan Stephan Sanders
- Department of Nephrology, University Medical Center Groningen, Groningen, The Netherlands
| | - Bouke G Hepkema
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Annechien J A Lambeck
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Laura B Bungener
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Caroline Roozendaal
- Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Marcel G J Tilanus
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Christina E Voorter
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Lotte Wieten
- Department of Transplantation Immunology, Tissue Typing Laboratory, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Elly M van Duijnhoven
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mariëlle A C J Gelens
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Maarten H L Christiaans
- Department of Internal Medicine, Division of Nephrology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Frans J van Ittersum
- Department of Nephrology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Shaikh A Nurmohamed
- Department of Nephrology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Neubury M Lardy
- Department of Immunogenetics, Sanquin Diagnostic Services, Amsterdam, The Netherlands
| | - Wendy Swelsen
- Department of Immunogenetics, Sanquin Diagnostic Services, Amsterdam, The Netherlands
| | - Karlijn A M I van der Pant
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Neelke C van der Weerd
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Ineke J M Ten Berge
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Andries Hoitsma
- Dutch Organ Transplant Registry (NOTR), Dutch Transplant Foundation (NTS), Leiden, The Netherlands
| | | | - Johan W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Michiel G H Betjes
- Department of Nephrology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Dave L Roelen
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frans H Claas
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frederike J Bemelman
- Renal Transplant Unit, Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Aleksandar Senev
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
| | - Maarten Naesens
- KU Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven University, Leuven, Belgium
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Sebastiaan Heidt
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Henny G Otten
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
- Central Diagnostic Laboratory (CDL), University Medical Center Utrecht, Utrecht, The Netherlands
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4
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Mubarak M, Raza A, Rashid R, Shakeel S. Evolution of human kidney allograft pathology diagnostics through 30 years of the Banff classification process. World J Transplant 2023; 13:221-238. [PMID: 37746037 PMCID: PMC10514746 DOI: 10.5500/wjt.v13.i5.221] [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: 04/10/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 09/15/2023] Open
Abstract
The second half of the previous century witnessed a tremendous rise in the number of clinical kidney transplants worldwide. This activity was, however, accompanied by many issues and challenges. An accurate diagnosis and appropriate management of causes of graft dysfunction were and still are, a big challenge. Kidney allograft biopsy played a vital role in addressing the above challenge. However, its interpretation was not standardized for many years until, in 1991, the Banff process was started to fill this void. Thereafter, regular Banff meetings took place every 2 years for the past 30 years. Marked changes have taken place in the interpretation of kidney allograft biopsies, diagnosis, and classification of rejection and other non-rejection pathologies from the original Banff 93 classification. This review attempts to summarize those changes for increasing the awareness and understanding of kidney allograft pathology through the eyes of the Banff process. It will interest the transplant surgeons, physicians, pathologists, and allied professionals associated with the care of kidney transplant patients.
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Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Amber Raza
- Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Rahma Rashid
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
| | - Shaheera Shakeel
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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5
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Bansal S, Arjuna A, Franz B, Guerrero-Alba A, Canez J, Fleming T, Rahman M, Hachem R, Mohanakumar T. Extracellular vesicles: a potential new player in antibody-mediated rejection in lung allograft recipients. FRONTIERS IN TRANSPLANTATION 2023; 2:1248987. [PMID: 38993876 PMCID: PMC11235353 DOI: 10.3389/frtra.2023.1248987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/22/2023] [Indexed: 07/13/2024]
Abstract
Identification of recipients with pre-existing antibodies and cross-matching of recipient sera with donor lymphocytes have reduced the incidence of antibody-mediated rejection (AMR) after human lung transplantation. However, AMR is still common and requires not only immediate intervention but also has long-term consequences including an increased risk of chronic lung allograft dysfunction (CLAD). The mechanisms resulting in AMR remain largely unknown due to the variation in clinical and histopathological features among lung transplant recipients; however, several reports have demonstrated a strong association between the development of antibodies against mismatched donor human leucocyte antigens [donor-specific antibodies (DSAs)] and AMR. In addition, the development of antibodies against lung self-antigens (K alpha1 tubulin and collagen V) also plays a vital role in AMR pathogenesis, either alone or in combination with DSAs. In the current article, we will review the existing literature regarding the association of DSAs with AMR, along with clinical diagnostic features and current treatment options for AMR. We will also discuss the role of extracellular vesicles (EVs) in the immune-related pathogenesis of AMR, which can lead to CLAD.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Ashwini Arjuna
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Brian Franz
- HLA Laboratory, Vitalant, Phoenix, AZ, United States
| | - Alexa Guerrero-Alba
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Jesse Canez
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Timothy Fleming
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Mohammad Rahman
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
| | - Ramsey Hachem
- Department of Surgery, Washington University, St. Louis, MO, United States
| | - T. Mohanakumar
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
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6
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Gibson B, Connelly C, Moldakhmetova S, Sheerin NS. Complement activation and kidney transplantation; a complex relationship. Immunobiology 2023; 228:152396. [PMID: 37276614 DOI: 10.1016/j.imbio.2023.152396] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 06/07/2023]
Abstract
Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement's role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.
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Affiliation(s)
- B Gibson
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - C Connelly
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - S Moldakhmetova
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK
| | - N S Sheerin
- Clinical and Translational Research Institute Faculty of Medical Sciences, Newcastle University Newcastle upon Tyne, NE2 4HH, UK.
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7
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Halverson LP, Hachem RR. Antibody-Mediated Rejection: Diagnosis and Treatment. Clin Chest Med 2023; 44:95-103. [PMID: 36774172 PMCID: PMC10148231 DOI: 10.1016/j.ccm.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Antibody-mediated rejection (AMR) is a form of lung allograft rejection that is emerging as an important risk factor for chronic lung allograft dysfunction and decreased long-term survival. In this review, we provide a brief overview of our current understanding of its pathophysiology with an emphasis on donor-specific antibodies before moving on to focus on the current diagnostic criteria and treatment strategies. Our goal is to discuss the limitations of our current knowledge and explore how novel diagnostic and therapeutic options aim to improve outcomes through earlier definitive diagnosis and preemptive targeted treatment.
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Affiliation(s)
- Laura P Halverson
- Division of Pulmonary & Critical Care, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63108, USA.
| | - Ramsey R Hachem
- Division of Pulmonary & Critical Care, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8052, Saint Louis, MO 63108, USA
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8
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Haas M, Mirocha J, Huang E, Najjar R, Peng A, Sethi S, Vo A, Anglicheau D, Jordan SC, Rabant M. A Banff-based histologic chronicity index is associated with graft loss in patients with a kidney transplant and antibody-mediated rejection. Kidney Int 2023; 103:187-195. [PMID: 36332728 PMCID: PMC11466365 DOI: 10.1016/j.kint.2022.09.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/19/2022] [Accepted: 09/16/2022] [Indexed: 11/15/2022]
Abstract
Antibody-mediated rejection (AMR) is the major cause of graft loss in kidney transplant recipients. The Banff classification defines two classes of AMR, active and chronic active but over time this classification has become increasingly complex. To simplify the approach to AMR, we developed activity and chronicity indices based on kidney transplant biopsy findings and examined their association with graft survival in 147 patients with active or chronic active AMR, all of whom had donor-specific antibodies and were treated for AMR. The activity index was determined as the sum of Banff glomerulitis (g), peritubular capillaritis (ptc), arteritis (v) and C4d scores, with a maximum score of 12. The chronicity index was the sum of interstitial fibrosis (ci), tubular atrophy (ct), chronic vasculopathy (cv), and chronic glomerulopathy (cg) scores, the latter doubled, with a maximum score of 15. While the activity index was generally not associated with graft loss, the chronicity index was significantly associated with graft loss with an optimal threshold value of 4 or greater for predicting graft loss. The association of the chronicity index of 4 or greater with graft loss was independent of other parameters associated with graft loss, including the estimated glomerular filtration rate at the time of biopsy, chronic active (versus active) AMR, AMR with de novo (versus persistent/rebound) donor-specific antibodies, Banff (g+ptc) scores, concurrent T cell-mediated rejection and donor-specific antibody reduction post-biopsy. The association of the chronicity index of 4 or greater with graft loss was confirmed in an independent cohort of 61 patients from Necker Hospital, Paris. Thus, our findings suggest that the chronicity index may be valuable as a simplified approach to decision-making in patients with AMR.
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Affiliation(s)
- Mark Haas
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
| | - James Mirocha
- General Clinical Research Center, Clinical & Translational Science Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Edmund Huang
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Reiad Najjar
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Alice Peng
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Supreet Sethi
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ashley Vo
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dany Anglicheau
- Deparment of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, AP-HP, INSERM U1151, Université Paris Cite, Paris, France
| | - Stanley C Jordan
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Marion Rabant
- Department of Pathology, Necker-Enfants Malades Hospital, AP-HP, Université Paris Cite, Paris, France
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9
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Franzin R, Stasi A, Sallustio F, Bruno S, Merlotti G, Quaglia M, Grandaliano G, Pontrelli P, Thurman JM, Camussi G, Stallone G, Cantaluppi V, Gesualdo L, Castellano G. Extracellular vesicles derived from patients with antibody-mediated rejection induce tubular senescence and endothelial to mesenchymal transition in renal cells. Am J Transplant 2022; 22:2139-2157. [PMID: 35583104 PMCID: PMC9546277 DOI: 10.1111/ajt.17097] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 01/25/2023]
Abstract
Extracellular vesicles (EV) are emerging mediators in several diseases. However, their role in the pathophysiology of antibody-mediated allograft rejection (AMR) has been poorly investigated. Here, we investigated the role of EV isolated from AMR patients in inducing tubular senescence and endothelial to mesenchymal transition (EndMT) and analyzed their miRNA expression profile. By multiplex bead flow cytometry, we characterized the immunophenotype of plasma AMR-derived EV and found a prevalent platelet and endothelial cell origin. In vitro, AMR-derived EV induced tubular senescence by upregulating SA-β Gal and CDKN1A mRNA. Furthermore, AMR-derived EV induced EndMT. The occurrence of tubular senescence and EndMT was confirmed by analysis of renal biopsies from the same AMR patients. Moreover, AMR-derived EV induced C3 gene upregulation and CFH downregulation in tubular epithelial cells, with C4d deposition on endothelial cells. Interestingly, RNase-mediated digestion of EV cargo completely abrogated tubular senescence and EndMT. By microarray analysis, miR-604, miR-515-3p, miR-let-7d-5p, and miR-590-3p were significantly upregulated in EV from AMR group compared with transplant controls, whereas miR-24-3p and miR-29a-3p were downregulated. Therefore, EV-associated miRNA could act as active player in AMR pathogenesis, unraveling potential mechanisms of accelerated graft senescence, complement activation and early fibrosis that might lead to new therapeutic intervention.
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Affiliation(s)
- Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ TransplantationUniversity of Bari Aldo MoroBariItaly
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ TransplantationUniversity of Bari Aldo MoroBariItaly
| | - Fabio Sallustio
- Interdisciplinary Department of Medicine (DIM)University of Bari "Aldo Moro"BariItaly
| | - Stefania Bruno
- Department of Medical Sciences and Molecular Biotechnology CenterUniversity of TorinoTorinoItaly
| | - Guido Merlotti
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine and Center for Autoimmune and Allergic Diseases (CAAD)University of Piemonte Orientale (UPO)NovaraItaly
| | - Marco Quaglia
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine and Center for Autoimmune and Allergic Diseases (CAAD)University of Piemonte Orientale (UPO)NovaraItaly
| | - Giuseppe Grandaliano
- Department Translational Medicine and SurgeryUniversità Cattolica Sacro CuoreRomeItaly
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ TransplantationUniversity of Bari Aldo MoroBariItaly
| | - Joshua M. Thurman
- Department of MedicineUniversity of Colorado School of MedicineAuroraColoradoUSA
| | - Giovanni Camussi
- Department of Medical Sciences and Molecular Biotechnology CenterUniversity of TorinoTorinoItaly
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical SciencesUniversity of FoggiaFoggiaItaly
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplantation Unit, Department of Translational Medicine and Center for Autoimmune and Allergic Diseases (CAAD)University of Piemonte Orientale (UPO)NovaraItaly
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ TransplantationUniversity of Bari Aldo MoroBariItaly
| | - Giuseppe Castellano
- Unit of NephrologyDialysis and Renal Transplantation ‐ Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico di MilanoMilanItaly
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10
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Yilmaz VT, Dandin O, Kisaoglu A, Avanaz A, Kamaci D, Toru HS, Demiryilmaz I, Koksoy S, Aydinli B, Kocak H. Prognosis and Treatment for Active and Chronic Antibody-Mediated Rejection in Renal Transplant Recipients; Single Center Experience. Transplant Proc 2022; 54:1809-1815. [PMID: 35907695 DOI: 10.1016/j.transproceed.2022.03.060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 03/01/2022] [Accepted: 03/26/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND The aim of the study was to evaluate the prognostic factors and treatment alternatives of antibody-mediated rejection (ABMR) in renal transplant patients. METHODS Three thousand renal transplant patients were included in the study. The patients were first divided into 2 groups. Group 1: ABMR [-] recipients (n = 2871), Group 2: ABMR (+) recipients (n = 129). ABMR patients were compared among themselves by dividing them into 3 subgroups (early-active, late-active, chronic-active). The study was performed retrospectively. Different combinations of methylprednisolone, intravenous immunoglobulin (IVIG), rituximab, plasmapheresis (PP), anti-thymocyte globulin (ATG) were used in the treatment and the results were compared. RESULTS Graft survival and functions were worse and the rates of CAD, delayed graft function, BK virus, and cytomegalovirus higher in patients with ABMR. Also, graft survival was lower in patients with serum creatinine ≥3 (P = 0.001), GFR <30 (P <0.001), and spot urine protein to creatinine ratio ≥1 (P = 0.042) at the time of diagnosis. High interstitial fibrosis and tubular atrophy scores in chronic ABMR cases and high intimal arteritis scores in active ABMR cases were poor prognostic factors. CONCLUSIONS The study showed that ABMR has a poor prognosis in terms of clinical parameters, and treatment should be individualized according to pathologic findings and graft functions at the time of diagnosis. Pulse methylprednisolone and IVIG should be used in the treatment of all ABMR patients, but PP, rituximab, and ATG should be used in selected cases. ABMR has a poor prognosis and treatment should be individualized.
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Affiliation(s)
- Vural Taner Yilmaz
- Department of Internal Medicine, Division of Nephrology, Akdeniz University Medical School, Antalya, Turkey.
| | - Ozgur Dandin
- Department of General Surgery, Akdeniz University Medical School, Antalya, Turkey
| | - Abdullah Kisaoglu
- Department of General Surgery, Akdeniz University Medical School, Antalya, Turkey
| | - Ali Avanaz
- Department of General Surgery, Akdeniz University Medical School, Antalya, Turkey
| | - Davut Kamaci
- Department of Urology, Ankara City Hospital, Ankara, Turkey
| | - Havva Serap Toru
- Department of Pathology, Akdeniz University Medical School, Antalya, Turkey
| | - Ismail Demiryilmaz
- Department of General Surgery, Akdeniz University Medical School, Antalya, Turkey
| | - Sadi Koksoy
- Department of Microbiology and Clinical Immunology, Akdeniz University Medical School, Antalya, Turkey
| | - Bulent Aydinli
- Department of General Surgery, Akdeniz University Medical School, Antalya, Turkey
| | - Huseyin Kocak
- Department of Internal Medicine, Division of Nephrology, Akdeniz University Medical School, Antalya, Turkey
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11
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Bestard O, Thaunat O, Bellini MI, Böhmig GA, Budde K, Claas F, Couzi L, Furian L, Heemann U, Mamode N, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Alloimmune Risk Stratification for Kidney Transplant Rejection. Transpl Int 2022; 35:10138. [PMID: 35669972 PMCID: PMC9163827 DOI: 10.3389/ti.2022.10138] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022]
Abstract
Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient's circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non-HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.
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Affiliation(s)
- Oriol Bestard
- Department of Nephrology and Kidney Transplantation, Vall d'Hebrón University Hospital, Barcelona, Spain
| | - Olivier Thaunat
- Department of Transplantation, Nephrology, and Clinical Immunology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | | | - Georg A Böhmig
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Frans Claas
- Eurotransplant Reference Laboratory, Department of Immunology, Leiden University Medical Center, Leiden, Netherlands
| | - Lionel Couzi
- Department of Nephrology, Transplantation and Dialysis, Bordeaux University Hospital, Bordeaux, France
| | - Lucrezia Furian
- Kidney and Pancreas Transplantation Unit, University of Padua, Padua, Italy
| | - Uwe Heemann
- Department of Nephrology, Technical University of Munich, Munich, Germany
| | - Nizam Mamode
- Department of Transplantation, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant, and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology, and Transplantation, KU Leuven, Leuven, Belgium
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12
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Roufosse C, Becker JU, Rabant M, Seron D, Bellini MI, Böhmig GA, Budde K, Diekmann F, Glotz D, Hilbrands L, Loupy A, Oberbauer R, Pengel L, Schneeberger S, Naesens M. Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation. Transpl Int 2022; 35:10140. [PMID: 35669973 PMCID: PMC9163810 DOI: 10.3389/ti.2022.10140] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/03/2022] [Indexed: 12/15/2022]
Abstract
Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.
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Affiliation(s)
- Candice Roufosse
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
| | - Jan Ulrich Becker
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Marion Rabant
- Department of Pathology, Hôpital Necker-Enfants Malades, Paris, France
| | - Daniel Seron
- Department of Nephrology and Kidney Transplantation, Vall d'Hebrón University Hospital, Barcelona, Spain
| | | | - Georg A Böhmig
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fritz Diekmann
- Department of Nephrology and Kidney Transplantation, Hospital Clinic Barcelona, Barcelona, Spain
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
| | - Rainer Oberbauer
- Division of Nephrology and Dialysis, Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
| | - Liset Pengel
- Centre for Evidence in Transplantation, University of Oxford, Oxford, United Kingdom
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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13
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Abstract
Rejection is a major complication following lung transplantation. Acute cellular rejection (ACR), and antibody-mediated rejection (AMR) are risk factors for the subsequent development of chronic lung allograft dysfunction and worse outcomes after transplantation. Although ACR has well-defined histopathologic diagnostic criteria and grading, the diagnosis of AMR requires a multidisciplinary diagnostic approach. This article reviews the identification, clinical and pathologic features of, and therapeutic options for ACR and AMR.
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Affiliation(s)
- Deborah J Levine
- Division of Pulmonary and Critical Care Medicine, University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Ramsey R Hachem
- Division of Pulmonary and Critical Care Medicine, Washington University in St. Louis, 4523 Clayton Avenue, Mailstop 8052-0043-14, St Louis, MO 63110, USA.
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14
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Nankivell BJ, P’Ng CH, Shingde M. Glomerular C4d Immunoperoxidase in Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy. Kidney Int Rep 2022; 7:1594-1607. [PMID: 35812271 PMCID: PMC9263257 DOI: 10.1016/j.ekir.2022.04.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 03/24/2022] [Accepted: 04/11/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction The diagnosis of late antibody-mediated rejection (AMR) is compromised by frequent absence of C4d in peritubular capillaries (C4dptc), termed “C4d-negative” AMR. We hypothesized that glomerular capillary C4d (C4dglom) reflected endothelial interaction with antibody and could improve immunologic classification of transplant glomerulopathy (TG). Methods We evaluated C4d using immunoperoxidase in 3524 consecutive, kidney transplant biopsies from a single center. Results C4dglom was detected in 16.5% and C4dptc in 9.9% of biopsies. C4dglom occurred in 60.3% of TG (n = 174) and was absent in normal glomeruli. Epidemiologic risk factors for C4dglom were younger, female, living-donor recipients with early AMR, prior treated rejection, and late presentation using multivariable analysis. Semiquantitative C4dglom score correlated with donor specific antibody (DSA) level, C4dptc, microvascular inflammation (MVI), Banff cg scores, renal dysfunction, and proteinuria. Principal component analysis colocalized C4dglom with histologic AMR. Multivariable analysis of TG found DSA, C4dptc, and post-transplant time associated with C4dglom. Addition of C4dglom into Banff chronic AMR schema improved its diagnostic sensitivity for TG (verified by electron microscopy [EM]) from 22.2% to 82.4% and accuracy from 59.6% to 93.9%, compared with Banff 2019 using only C4dptc. Tissue C4dglom and chronic AMR diagnosis incorporating C4dglom were associated with death-censored allograft failure in TG (P < 0.001), independent of the severity of glomerulopathy and chronic interstitial fibrosis. Conclusion C4dglom is a promising diagnostic biomarker of endothelial interaction with antibody which substantially improved test performance of the Banff schema to correctly classify TG by pathophysiology and prognosticate graft loss. We recommend routine C4d immunoperoxidase to minimize underdiagnosis of late AMR in TG.
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Affiliation(s)
- Brian J. Nankivell
- Department of Renal Medicine, Westmead Hospital, Sydney, New South Wales, Australia
- Correspondence: Brian J. Nankivell, Department of Renal Medicine, Westmead Hospital, Westmead, Sydney, 2145 New South Wales, Australia.
| | - Chow H. P’Ng
- Department of Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Sydney, New South Wales, Australia
| | - Meena Shingde
- Department of Tissue Pathology and Diagnostic Oncology, Institute of Clinical Pathology and Medical Research, Sydney, New South Wales, Australia
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15
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Qi R, Qin W. Role of Complement System in Kidney Transplantation: Stepping From Animal Models to Clinical Application. Front Immunol 2022; 13:811696. [PMID: 35281019 PMCID: PMC8913494 DOI: 10.3389/fimmu.2022.811696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/31/2022] [Indexed: 12/23/2022] Open
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Novel insights highlighted the role of the locally produced and intracellular complement components in the development of inflammation and the alloreactive response in the kidney allograft. In the current review, we provide the updated understanding of the complement system in kidney transplantation. We will discuss the involvement of the different complement components in kidney ischemia-reperfusion injury, delayed graft function, allograft rejection, and chronic allograft injury. We will also introduce the existing and upcoming attempts to improve allograft outcomes in animal models and in the clinical setting by targeting the complement system.
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Affiliation(s)
| | - Weijun Qin
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
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16
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Koslik MA, Friebus-Kardash J, Heinemann FM, Kribben A, Bräsen JH, Eisenberger U. Differential Treatment Effects for Renal Transplant Recipients With DSA-Positive or DSA-Negative Antibody-Mediated Rejection. Front Med (Lausanne) 2022; 9:816555. [PMID: 35174191 PMCID: PMC8841765 DOI: 10.3389/fmed.2022.816555] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/07/2022] [Indexed: 12/22/2022] Open
Abstract
Background Antibody-mediated rejection (ABMR) is the main cause of renal allograft loss. The most common treatment strategy is based on plasmapheresis plus the subsequent administration of intravenous immunoglobulin (IVIG). Unfortunately, no approved long-term therapy is available for ABMR. The current study was designed to analyze the effect of various ABMR treatment approaches on allograft survival and to compare treatment effects in the presence or absence of donor-specific antibodies (DSAs). Methods This single-center study retrospectively analyzed 102 renal allograft recipients who had biopsy-proven ABMR after transplant. DSA was detectable in 61 of the 102 patients. Initial standard treatment of ABMR consisted of plasmapheresis (PS) or immunoadsorption (IA), followed by a single course of IVIG. In case of nonresponse or recurrence, additional immunosuppressive medications, such as rituximab, bortezomib, thymoglobulin, or eculizumab, were administered. In a second step, persistent ABMR was treated with increased maintenance immunosuppression, long-term therapy with IVIG (more than 1 year), or both. Results Overall graft survival among transplant patients with ABMR was <50% after 3 years of follow-up. Compared to the use of PS/IA and IVIG alone, the use of additional immunosuppressive medications had no beneficial effect on allograft survival (p = 0.83). Remarkably, allografts survival rates were comparable between patients treated with the combination of PS/IA and IVIG and those treated with a single administration of IVIG (p = 0.18). Renal transplant patients with ABMR but without DSAs benefited more from increased maintenance immunosuppression than did DSA-positive patients with ABMR (p = 0.01). Recipients with DSA-positive ABMR exhibited significantly better allograft survival after long-term application of IVIG for more than 1 year than did recipients with DSA-negative ABMR (p = 0.02). Conclusions The results of our single-center cohort study involving kidney transplant recipients with ABMR suggest that long-term application of IVIG is more favorable for DSA-positive recipients, whereas intensification of maintenance immunosuppression is more effective for recipients with DSA-negative ABMR.
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Affiliation(s)
- Marius Andreas Koslik
- Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Justa Friebus-Kardash
- Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Falko Markus Heinemann
- Institute for Transfusion Medicine, Transplantation Diagnostics, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Andreas Kribben
- Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jan Hinrich Bräsen
- Nephropathology Unit, Hannover Medical School, Institute of Pathology, Hanover, Germany
| | - Ute Eisenberger
- Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Ute Eisenberger
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17
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Donor-derived Cell-free DNA Complements De Novo Class II DSA in Detecting Late Alloimmune Injury Post Kidney Transplantation. Transplant Direct 2022; 8:e1285. [PMID: 35187211 PMCID: PMC8806361 DOI: 10.1097/txd.0000000000001285] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/17/2021] [Accepted: 11/30/2021] [Indexed: 01/09/2023] Open
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18
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Loupy A, Mengel M, Haas M. 30 years of the International Banff Classification for Allograft Pathology: The Past, Present and Future of Kidney Transplant Diagnostics. Kidney Int 2021; 101:678-691. [DOI: 10.1016/j.kint.2021.11.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/06/2021] [Accepted: 11/05/2021] [Indexed: 10/19/2022]
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19
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Lee BT, Fiel MI, Schiano TD. Antibody-mediated rejection of the liver allograft: An update and a clinico-pathological perspective. J Hepatol 2021; 75:1203-1216. [PMID: 34343613 DOI: 10.1016/j.jhep.2021.07.027] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 07/06/2021] [Accepted: 07/14/2021] [Indexed: 12/16/2022]
Abstract
Antibody-mediated rejection after liver transplantation is an under-recognised cause of allograft injury. While definitions of acute and chronic antibody-mediated rejection have increased clinical awareness, timely identification and management of antibody-mediated rejection remain difficult because of complexities in diagnosis and histopathology, lack of treatment protocols, and unclear long-term outcomes. While recent cohort studies assessing the importance of donor-specific antibodies have aided in its diagnosis, literature on the treatment of antibody-mediated rejection in liver transplantation remain limited to case reports and small series. Further increasing the awareness and timely recognition of antibody-mediated rejection post-liver transplantation is crucial in order to stimulate future research and the development of protocols for its diagnosis and treatment. This review will summarise recent advances in the clinical diagnosis and treatment of antibody-mediated rejection in liver transplantation, as well as some of the histopathologic features (on liver biopsy tissue) of acute and chronic antibody-mediated rejection.
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Affiliation(s)
- Brian T Lee
- Division of Gastroenterology and Transplant Institute, Loma Linda University Health, Loma Linda, CA, USA.
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Thomas D Schiano
- Division of Liver Diseases, Department of Medicine, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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20
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Yu MY, Kwon S, Moon JJ, Kim YC, Song EY, Lee H, Moon KC, Ha J, Kim DK, Han SW, Kim GH, Kim YS, Yang SH. Role of the IL-33/ST2 pathway in renal allograft rejection. Exp Cell Res 2021; 405:112705. [PMID: 34166678 DOI: 10.1016/j.yexcr.2021.112705] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 06/04/2021] [Accepted: 06/09/2021] [Indexed: 11/25/2022]
Abstract
The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) pathway modulates immune response and inflammation, associated with allograft dysfunction and rejection. We hypothesized that IL-33/ST2 is a marker of renal allograft rejection and IL-33/ST2 expression may differ according to rejection type. IL-33/ST2 expression was measured in sera and kidney tissues from recipients with acute antibody-mediated rejection (AAMR), acute cell-mediated rejection (ACMR), chronic antibody-mediated rejection (CAMR), and healthy controls. The soluble ST2 and IL-33/ST2 expression levels were higher in participants with all three rejection types than in controls. Although the expression levels in recipients with AAMR and ACMR were significantly higher than those with CAMR, there was no significant difference between the expression levels in AAMR and ACMR. Although IL-33, IL-8, and fibronectin expression were significantly increased after the addition of the recipients' serum in primary cultured human renal proximal tubular epithelial cells, the levels decreased after treatment with an anti-ST2 antibody. Furthermore, the anti-ST2 antibody specifically suppressed the upregulation of the mixed lymphocyte reaction. Boyden chamber assays demonstrated that anti-ST2 antibody abrogated chemotaxis induced by recombinant IL-33. Thus, IL-33 and ST2 are potent mediators of rejection. Treatment with an anti-ST2 antibody ameliorates rejection and could be a potential therapeutic strategy for renal allograft rejection.
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Affiliation(s)
- Mi-Yeon Yu
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, South Korea; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Soie Kwon
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Jong Joo Moon
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Yong-Chul Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Eun Young Song
- Department of Laboratory Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Hajeong Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyung Chul Moon
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Department of Pathology, Seoul National University Hospital, Seoul, South Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Dong Ki Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Sang-Woong Han
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, South Korea; Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Gheun-Ho Kim
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, South Korea
| | - Yon Su Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung Hee Yang
- Kidney Research Institute, Seoul National University College of Medicine, Seoul, South Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
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21
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Akdogan N, Ersoy-Evans S, Gokoz O, Erdem Y, Nasir S. Early recognition of chronic rejection in a face allotransplant patient with alopecia. J Cutan Pathol 2021; 48:1286-1297. [PMID: 34085296 DOI: 10.1111/cup.14069] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 04/06/2021] [Accepted: 05/30/2021] [Indexed: 11/26/2022]
Abstract
The features of chronic rejection (CR) in full-face vascularized composite allotransplantation (VCA) are not well-known. Herein, we report a full-face transplant patient that experienced two episodes of acute rejection (AR) and three episodes of AR/CR over the course of 6-years. The patient noticed a small, round patch of hair loss in his beard 9 months after the second AR episode, which occurred 21 months post-transplantation. Biopsy of the alopecic patch showed lichen-planopilaris-like features, which was suggestive of early CR. Despite an increase in immunosuppressive dosages, the alopecia progressed. Following the second and third AR/CR episodes, the alopecia became more pronounced, with the addition of hyperpigmentation as well as sclerosis and telangiectasia. The findings of multiple biopsies showed CR. Based on these findings we think that alopecia with lichen-planopilaris-like histopathological features similar to grade III AR features, particularly in hair follicles appears to be an early finding of CR in the presented patient. The findings further indicate that follicular involvement may be a significant feature of CR in VCA patients and that it can present prior to sclerosis, vasculopathy, or loss of adnexa. The present case is uniquely important because of the distinctive presentation of CR, with hair follicles clinically and histopathologically affected, leading to progressive and irreversible alopecia with lichen-planopilaris-like histopathology.
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Affiliation(s)
- Neslihan Akdogan
- Department of Dermatology, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Sibel Ersoy-Evans
- Department of Dermatology, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Ozay Gokoz
- Department of Pathology, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Yunus Erdem
- Department of Nephrology, School of Medicine, Hacettepe University, Ankara, Turkey
| | - Serdar Nasir
- Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Hacettepe University, Ankara, Turkey
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22
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Halverson LP, Hachem RR. Antibody-Mediated Rejection and Lung Transplantation. Semin Respir Crit Care Med 2021; 42:428-435. [PMID: 34030204 DOI: 10.1055/s-0041-1728796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Antibody-mediated rejection (AMR) is now a widely recognized form of lung allograft rejection, with mounting evidence for AMR as an important risk factor for the development of chronic lung allograft dysfunction and markedly decreased long-term survival. Despite the recent development of the consensus diagnostic criteria, it remains a challenging diagnosis of exclusion. Furthermore, even after diagnosis, treatment directed at pulmonary AMR has been nearly exclusively derived from practices with other solid-organ transplants and other areas of medicine, such that there is a significant lack of data regarding the efficacy for these in pulmonary AMR. Lastly, outcomes after AMR remain quite poor despite aggressive treatment. In this review, we revisit the history of AMR in lung transplantation, describe our current understanding of its pathophysiology, discuss the use and limitations of the consensus diagnostic criteria, review current treatment strategies, and summarize long-term outcomes. We conclude with a synopsis of our most pressing gaps in knowledge, introduce recommendations for future directions, and highlight promising areas of active research.
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Affiliation(s)
- Laura P Halverson
- Division of Pulmonary and Critical Care, Washington University School of Medicine, Saint Louis, Missouri
| | - Ramsey R Hachem
- Division of Pulmonary and Critical Care, Washington University School of Medicine, Saint Louis, Missouri
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23
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Eleftheriadis T, Pissas G, Crespo M, Filippidis G, Antoniadis N, Liakopoulos V, Stefanidis I. The effect of anti‑HLA class I antibodies on the immunological properties of human glomerular endothelial cells and their modification by mTOR inhibition or GCN2 kinase activation. Mol Med Rep 2021; 23:355. [PMID: 33760196 PMCID: PMC7974416 DOI: 10.3892/mmr.2021.11994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/26/2021] [Indexed: 11/06/2022] Open
Abstract
In antibody‑mediated rejection (ABMR), the graft endothelium is at the forefront of the kidney transplant against the assault from the recipient's humoral immune system, and is a target of the latter. The present study investigated the effect of antibodies against human leukocyte antigen (HLA) class I (anti‑HLAI) on the immunological properties of human glomerular endothelial cells. Additionally, the effect of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) inhibitor (everolimus), or the general control nonderepressible 2 kinase (GCN2K) activator (halofuginone) on anti‑HLAI antibody‑mediated alterations was assessed. Cell integrity was examined, an lactate dehydrogenase (LDH) release assay was performed and cleaved caspase‑3 levels were determined. Furthermore, cell proliferation was analyzed by performing a bromodeoxyuridine assay and the cellular proteins involved in signal transduction or immune effector mechanisms were assessed via western blotting. IL‑8, monocyte chemoattractive protein‑1 (MCP‑1), von Willebrand factor (vWF) and transforming growth factor‑beta 1 (TGF‑β1) were assayed via ELISA. The results revealed that anti‑HLAI triggered integrin signaling, activated mTOR and GCN2K, preserved cell integrity and promoted cell proliferation. Additionally, by increasing intercellular adhesion molecule 1 (ICAM‑1), HLA‑DR, IL‑8 and MCP‑1 levels, anti‑HLAI enhanced the ability of immune cells to interact with endothelial cells thus facilitating graft rejection. Contrarily, by upregulating CD46 and CD59, anti‑HLAI rendered the endothelium less vulnerable to complement‑mediated injury. Finally, by enhancing vWF and TGF‑β1, anti‑HLAI may render the endothelium prothrombotic and facilitate fibrosis and graft failure, respectively. According to our results, mTORC1 inhibition and GCN2K activation may prove useful pharmaceutical targets, as they prevent cell proliferation and downregulate ICAM‑1, IL‑8, MCP‑1 and TGF‑β1. mTORC1 inhibition also decreases vWF.
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Affiliation(s)
- Theodoros Eleftheriadis
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa 41110, Greece
| | - Georgios Pissas
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa 41110, Greece
| | - Marta Crespo
- Nephrology Department, Hospital del Mar, Mar Health Park, Hospital del Mar Medical Research Institute, Barcelona 08003, Spain
| | - Georgios Filippidis
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa 41110, Greece
| | - Nikolaos Antoniadis
- Organ Transplant Unit, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Greece
| | - Vassilios Liakopoulos
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa 41110, Greece
| | - Ioannis Stefanidis
- Department of Nephrology, Faculty of Medicine, University of Thessaly, Larissa 41110, Greece
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24
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Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group. Transplantation 2020; 104:911-922. [PMID: 31895348 PMCID: PMC7176344 DOI: 10.1097/tp.0000000000003095] [Citation(s) in RCA: 218] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.
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25
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Verleden SE, Von der Thüsen J, Roux A, Brouwers ES, Braubach P, Kuehnel M, Laenger F, Jonigk D. When tissue is the issue: A histological review of chronic lung allograft dysfunction. Am J Transplant 2020; 20:2644-2651. [PMID: 32185874 DOI: 10.1111/ajt.15864] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/03/2020] [Accepted: 03/05/2020] [Indexed: 01/25/2023]
Abstract
Although chronic lung allograft dysfunction (CLAD) remains the major life-limiting factor following lung transplantation, much of its pathophysiology remains unknown. The discovery that CLAD can manifest both clinically and morphologically in vastly different ways led to the definition of distinct subtypes of CLAD. In this review, recent advances in our understanding of the pathophysiological mechanisms of the different phenotypes of CLAD will be discussed with a particular focus on tissue-based and molecular studies. An overview of the current knowledge on the mechanisms of the airway-centered bronchiolitis obliterans syndrome, as well as the airway and alveolar injuries in the restrictive allograft syndrome and also the vascular compartment in chronic antibody-mediated rejection is provided. Specific attention is also given to morphological and molecular markers for early CLAD diagnosis or histological changes associated with subsequent CLAD development. Evidence for a possible overlap between different forms of CLAD is presented and discussed. In the end, "tissue remains the (main) issue," as we are still limited in our knowledge about the actual triggers and specific mechanisms of all late forms of posttransplant graft failure, a shortcoming that needs to be addressed in order to further improve the outcome of lung transplant recipients.
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Affiliation(s)
- Stijn E Verleden
- Lab of Respiratory Diseases, BREATH, Department of CHROMETA, KU Leuven, Leuven, Belgium.,Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany
| | - Jan Von der Thüsen
- Department of Pathology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Antoine Roux
- Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
| | - Emily S Brouwers
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Peter Braubach
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Mark Kuehnel
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Florian Laenger
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
| | - Danny Jonigk
- Institute of Pathology, Hannover Medical School (MHH), Hanover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), The German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL), Hannover Medical School (MHH), Hannover, Germany
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26
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Kasuno K, Nishimori K, Yokoi S, Shimamoto Y, Sakashita S, Morita S, Nishikawa S, Nishikawa Y, Kobayashi M, Fukushima S, Mikami D, Takahashi N, Oota Y, Kimura H, Iwano M. Preemptive HLA Antibody Screening Prior to Episodic Transplant Renal Biopsy Enables Early Diagnosis and Therapeutic Response in Asymptomatic Chronically Active Antibody-Related Rejection: A Case Report. Transplant Proc 2020; 52:2750-2753. [PMID: 32951864 DOI: 10.1016/j.transproceed.2020.08.034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/28/2020] [Accepted: 08/12/2020] [Indexed: 11/19/2022]
Abstract
Common management of renal transplant recipients includes episodic renal biopsy based on clinical findings such as an increase in proteinuria or serum creatinine. When antibody-related rejection is suspected from the renal biopsy, subsequent testing for donor-specific antibodies (DSAs) is performed. We instead performed preemptive screening of asymptomatic post-renal transplant recipients for DSAs prior to renal biopsy. In this case, a 30-year-old woman with a secondary transplant was positive for 61 anti-HLA antibodies of class I and class II, among which DQ2 was a DSA with a mean fluorescence index of 2039. The patient had a living kidney transplant 9 years earlier. She had never been diagnosed with rejection, her serum creatinine was around 1.0 mg/dL, and her proteinuria was negative. Following the positive DSA result, a renal biopsy was performed, and she was diagnosed as C4d-negative chronic-active antibody-mediated rejection (CAABMR) with a Banff score of cg1b, (g + ptc) ≥ 2, and C4d 0. Intravenous steroid pulse, deoxyspagarin, antithymocyte globulin, rituximab, and oral everolimus were administrated. The treatment resulted in a gradual decrease in the DSA, which became negative 1 year later. The patient's serum creatinine remains around 1.0 mg/dL, and proteinuria remains negative. Treatments for advanced CAABMR are often expensive and ineffective. Our present case suggests that early detection and treatment through preemptive HLA antibody screening could improve the prognosis of renal transplants.
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Affiliation(s)
- Kenji Kasuno
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
| | - Kazuhisa Nishimori
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Seiji Yokoi
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yuki Shimamoto
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Sayumi Sakashita
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Sayu Morita
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Sho Nishikawa
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yudai Nishikawa
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Mamiko Kobayashi
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Sachiko Fukushima
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Daisuke Mikami
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Naoki Takahashi
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Yumiko Oota
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Hideki Kimura
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Masayuki Iwano
- Department of Nephrology, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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27
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Franzin R, Stasi A, Fiorentino M, Stallone G, Cantaluppi V, Gesualdo L, Castellano G. Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage. Front Immunol 2020; 11:734. [PMID: 32457738 PMCID: PMC7221190 DOI: 10.3389/fimmu.2020.00734] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney's excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16 ink4a , Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.
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Affiliation(s)
- Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Vincenzo Cantaluppi
- Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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28
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Bhalla A, Alachkar N, Alasfar S. Complement-Based Therapy in the Management of Antibody-Mediated Rejection. Adv Chronic Kidney Dis 2020; 27:138-148. [PMID: 32553246 DOI: 10.1053/j.ackd.2019.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 12/11/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Antibody-mediated rejection (AMR) is one of the leading causes of kidney allograft failure and is usually mediated by anti-human leukocyte antigen donor-specific antibodies (DSAs). Activation of classical pathway of the complement system is responsible for downstream effects of DSA and account for significant manifestations of AMR. Currently, the treatment of AMR is based on strategies to remove preformed antibodies or to prevent their production; however, these strategies are often unsuccessful. It is theoretically possible to inhibit complement activity to prevent the effect of DSA on kidney allograft function. Complement inhibitors such as eculizumab, a complement 5 monoclonal antibody, and complement 1 esterase inhibitors (C1 INHs) have been used in prevention and treatment of AMR with variable success. Eculizumab and C1 INH seem to reduce the incidence of early AMR and allow transplantation in highly sensitized kidney transplant recipients, but data on their long-term effect on kidney allograft function are limited. Several case reports described the successful use of eculizumab in the treatment of AMR, but there are no randomized controlled studies that showed efficacy. Treatment of AMR with C1 INH, in addition to standard of care, did not change short-term outcome but long-term studies are underway.
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29
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Holscher CM, Jackson KR, Segev DL. Transplanting the Untransplantable. Am J Kidney Dis 2020; 75:114-123. [DOI: 10.1053/j.ajkd.2019.04.025] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 04/22/2019] [Indexed: 12/27/2022]
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30
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Hachem RR. The role of the immune system in lung transplantation: towards improved long-term results. J Thorac Dis 2019; 11:S1721-S1731. [PMID: 31632749 DOI: 10.21037/jtd.2019.04.25] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Over the past 35 years, lung transplantation has evolved from an experimental treatment to the treatment of choice for patients with end-stage lung disease. Beyond the immediate period after lung transplantation, rejection and infection are the leading causes of death. The risk of rejection after lung transplantation is generally higher than after other solid organ transplants, and this necessitates more intensive immunosuppression. However, this more intensive treatment does not reduce the risk of rejection sufficiently, and rejection is one of the most common complications after transplantation. There are multiple forms of rejection including acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction. These have posed a vexing problem for clinicians, patients, and the field of lung transplantation. Confounding matters is the inherent effect of more intensive immunosuppression on the risk of infections. Indeed, infections pose a direct problem resulting in morbidity and mortality and increase the risk of chronic lung allograft dysfunction in the ensuing weeks and months. There are complex interactions between microbes and the immune response that are the subject of ongoing studies. This review focuses on the role of the immune system in lung transplantation and highlights different forms of rejection and the impact of infections on outcomes.
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Affiliation(s)
- Ramsey R Hachem
- Division of Pulmonary & Critical Care, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
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31
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Abstract
The human major histocompatibility complex is a family of genes that encodes HLAs, which have a crucial role in defence against foreign pathogens and immune surveillance of tumours. In the context of transplantation, HLA molecules are polymorphic antigens that comprise an immunodominant alloreactive trigger for the immune response, resulting in rejection. Remarkable advances in knowledge and technology in the field of immunogenetics have considerably enhanced the safety of transplantation. However, access to transplantation among individuals who have become sensitized as a result of previous exposure to alloantigens is reduced proportional to the breadth of their sensitization. New approaches for crossing the HLA barrier in transplantation using plasmapheresis, intravenous immunoglobulin and kidney paired donation have been made possible by the relative ease with which even low levels of anti-HLA antibodies can now be detected and tracked. The development of novel protocols for the induction of tolerance and new approaches to immunomodulation was also facilitated by advances in HLA technology. Here, we review the progress made in understanding HLAs that has enabled organ transplantation to become a life-saving endeavour that is accessible even for sensitized patients. We also discuss novel approaches to desensitization, immunomodulation and tolerance induction that have the potential to further improve transplantation access and outcomes.
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32
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Parajuli S, Redfield RR, Garg N, Aziz F, Mohamed M, Astor BC, Zhong W, Djamali A, Mandelbrot DA. Clinical Significance of Microvascular Inflammation in the Absence of Anti-HLA DSA in Kidney Transplantation. Transplantation 2019; 103:1468-1476. [PMID: 30335696 DOI: 10.1097/tp.0000000000002487] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Limited information exists about outcomes of HLA donor-specific antibody (DSA) negative (DSA-) microvascular inflammation (MVI). METHODS We report our experience with 25 DSA- patients with MVI compared to 155 DSA+ patients who met Banff 2013 criteria for antibody-mediated rejection (AMR). We also compared outcomes to 228 DSA+ patients whose biopsies were negative for rejection and served as a negative control. RESULTS There were no significant differences in the baseline characteristics between the DSA- MVI and DSA+ AMR groups. At the time of diagnosis, both groups had similar graft function. The DSA- group had higher MVI scores but lower C4d scores. At last follow-up, renal function was similar between the groups. There were 12 (48%) graft failures in the DSA- group and 59 (38%) graft failures in the DSA+ group, which was not statistically different. Similar results were found after matching for the MVI scores, C4d, and treatment between 2 groups. We also found similar outcomes between DSA- and DSA+ patients when only including those who would have met Banff 2017 criteria for AMR. In univariate Cox regression analyses, estimated glomerular filtration rate at time of biopsy, glomerulitis, rituximab, diabetes, v score, allograft glomerulopathy, fibrous intimal thickening, tubular atrophy, and interstitial fibrosis scores were associated with graft failure. In multivariate analysis, only estimated glomerular filtration rate was protective. Both groups had significantly worse outcomes than the DSA+-negative controls without AMR. CONCLUSIONS Our findings suggest that outcomes and response to treatment with HLA DSA- MVI patients are similarly poor to those with DSA+ MVI patients, supporting a critical role for MVI in the diagnosis of AMR.
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Affiliation(s)
- Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Robert R Redfield
- Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Maha Mohamed
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Brad C Astor
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
- Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weixong Zhong
- Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Arjang Djamali
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
- Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Didier A Mandelbrot
- Division of Nephrology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
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33
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Detection of Complement-binding Donor-specific Antibodies, Not IgG-antibody Strength Nor C4d Status, at Antibody-mediated Rejection Diagnosis Is an Independent Predictor of Kidney Graft Failure. Transplantation 2019; 102:1943-1954. [PMID: 29757900 DOI: 10.1097/tp.0000000000002265] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Antibody-mediated rejection (AMR) remains associated with reduced kidney graft survival and no clear prognostic marker is available. METHODS We investigated whether donor-specific antibodies (DSA) ability to bind C1q in comparison with AMR C4d status, both indirect signs of complement activation, improve risk stratification at time of AMR. Hence, among 467 patients in whom 1 or more graft biopsies were performed between 2008 and 2015, we included 56 with AMR according to Banff '15 criteria. Using concurrent sera, we prospectively identified DSA by single-antigen beads (IgG and C1q) assays. RESULTS Antibody-mediated rejection C4d (+) (n = 28) was associated with preformed DSA (P = 0.007), whereas DSA C1q (+) (n = 25) cases had stronger IgG-DSA (P < 0.001). At AMR, graft function was similar between DSA C1q groups, but in the first year after, it improved in DSA C1q (-), whereas a steady decline was observed in DSA C1q (+) cases, remaining significantly lower from 1 year until 4 years after AMR. DSA C1q (+) was significantly associated with reduced graft survival (P = 0.021), whereas AMR C4d (+) was not (P = 0.550). Importantly, a similar negative impact of DSA C1q (+) on graft survival was observed within AMR C4d (+) (P = 0.040) and (-) (P = 0.036), cases. In multivariable analysis, DSA C1q (+) (hazard ratio, 3.939, P = 0.005) and de novo DSA (hazard ratio, 4.409, P = 0.033) were independent predictors of graft failure, but stronger IgG-DSA was not. Similar results were obtained considering C1q-DSA and IgG-DSA strength as continuous variables. CONCLUSIONS C1q-DSA assessment at AMR can be a valuable tool in detecting patients with higher risk of graft failure.
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Ngo C, Danel C, Duong-Quy S, Dauriat G, Castier Y, Lortat-Jacob B, Mal H, Brugière O, Cazes A. C4d detection and histological patterns in the diagnosis of antibody-mediated rejection after lung transplantation: a single-centre study. Histopathology 2019; 74:988-996. [PMID: 30636056 DOI: 10.1111/his.13823] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Accepted: 01/10/2019] [Indexed: 12/27/2022]
Abstract
AIMS Antibody-mediated rejection (AMR) is an emerging and challenging issue in transplantation. Endothelial deposition of C4d and microvascular inflammation (MI) are reliable markers of AMR in renal and cardiac transplantation, but remain controversial in the lung. Our aim was to assess C4d immunohistochemistry and histological patterns for the diagnosis of lung AMR. METHODS AND RESULTS We reviewed 158 transbronchial biopsies (TBBs) (n = 85 clinically indicated, and n = 73 surveillance TBBs) from 48 recipients, blinded to clinical and serological data. C4d was scored as 0, 1+ (<10%), 2+ (10-50%) or 3+ (>50%). TBBs were reassessed for MI and acute lung injury (ALI). Donor-specific antibodies (DSAs), acute clinical graft dysfunction and chronic lung allograft graft dysfunction (CLAD) were recorded. C4d3+, C4d2+, C4d1+ and C4d0 occurred respectively in four (2.5%), six (3.8%), 28 (17.7%) and 120 (75.9%) TBBs. MI and ALI were rare but more frequent in C4d1-3+ TBBs than in the absence of C4d. C4d2+ was frequently observed with concomitant infection. Among the surveillance TBBs, only two (2.7%) showed MI. Neither ALI nor C4d3+ was diagnosed on surveillance TBBs. No significant association was found between histopathological findings and DSAs. All four patients with C4d3+ could retrospectively be diagnosed with AMR and developed CLAD. CONCLUSION Although rare, diffuse C4d deposition appears to be a strong indication of acute clinical AMR in lung transplant patients, whereas intermediate C4d2+ requires more investigations. In stable patients, histopathology and C4d may lack the sensitivity to diagnose subclinical AMR. This emphasises the need for a multidisciplinary evaluation of each suspected AMR case, and the need for complementary diagnostic tools.
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Affiliation(s)
- Carine Ngo
- Département de Pathologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Claire Danel
- Département de Pathologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.,INSERM U1152, Paris Diderot University, Paris, France
| | - Sy Duong-Quy
- Department of Lung Function Testing, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France
| | - Gaëlle Dauriat
- Service de Pneumologie B et Transplantation, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Yves Castier
- INSERM U1152, Paris Diderot University, Paris, France.,Service de Chirurgie Vasculaire et Thoracique, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Brice Lortat-Jacob
- Service de Réanimation Chirurgicale, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Hervé Mal
- INSERM U1152, Paris Diderot University, Paris, France.,Service de Pneumologie B et Transplantation, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Olivier Brugière
- INSERM U1152, Paris Diderot University, Paris, France.,Service de Pneumologie B et Transplantation, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.,Service de Pneumologie et Transplantation, Hôpital Foch, Suresnes, France
| | - Aurélie Cazes
- Département de Pathologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France.,INSERM U1152, Paris Diderot University, Paris, France
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35
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Goutaudier V, Perrochia H, Mucha S, Bonnet M, Delmas S, Garo F, Garrigue V, Lepreux S, Pernin V, Serre JE, Szwarc I, Merville P, Ramounau-Pigot A, René C, Visentin J, Morgan BP, Frémeaux-Bacchi V, Mourad G, Couzi L, Le Quintrec M. C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection. Front Immunol 2019; 10:235. [PMID: 30906289 PMCID: PMC6418012 DOI: 10.3389/fimmu.2019.00235] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/28/2019] [Indexed: 12/17/2022] Open
Abstract
C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.
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Affiliation(s)
- Valentin Goutaudier
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Hélène Perrochia
- Department of Pathology, Gui de Chauliac Hospital, Montpellier University Hospital, Montpellier, France
| | - Simon Mucha
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin Hospital, Bordeaux University Hospital, Bordeaux, France
| | - Marie Bonnet
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Sylvie Delmas
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Florian Garo
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Valérie Garrigue
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Sébastien Lepreux
- Department of Pathology, Pellegrin Hospital, Bordeaux University Hospital, Bordeaux, France
| | - Vincent Pernin
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France.,INSERM U1183, Institute for Regenerative Medicine and Biotherapy, Saint-Eloi Hospital, Montpellier University Hospital, Montpellier, France
| | - Jean-Emmanuel Serre
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Ilan Szwarc
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Pierre Merville
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin Hospital, Bordeaux University Hospital, Bordeaux, France.,UMR CNRS 5164, ImmunoConcEpT, Bordeaux University, Bordeaux, France
| | - Annie Ramounau-Pigot
- Department of Immunology, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
| | - Céline René
- Department of Immunology, Saint Eloi Hospital, Montpellier University Hospital, Montpellier, France
| | - Jonathan Visentin
- UMR CNRS 5164, ImmunoConcEpT, Bordeaux University, Bordeaux, France.,Department of Immunology and Immunogenetics, Pellegrin Hospital, Bordeaux University Hospital, Bordeaux, France
| | - Bryan Paul Morgan
- School of Medicine, Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom
| | | | - Georges Mourad
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France
| | - Lionel Couzi
- Department of Nephrology, Transplantation, Dialysis and Apheresis, Pellegrin Hospital, Bordeaux University Hospital, Bordeaux, France.,UMR CNRS 5164, ImmunoConcEpT, Bordeaux University, Bordeaux, France
| | - Moglie Le Quintrec
- University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France.,INSERM U1183, Institute for Regenerative Medicine and Biotherapy, Saint-Eloi Hospital, Montpellier University Hospital, Montpellier, France
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36
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Doreille A, Dieudé M, Cardinal H. The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients. Am J Physiol Renal Physiol 2018; 316:F9-F19. [PMID: 30379097 DOI: 10.1152/ajprenal.00163.2018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Independent of the initial cause of kidney disease, microvascular injury to the peritubular capillary network appears to play a central role in the development of interstitial fibrosis in both native and transplanted kidney disease. This association is explained by mechanisms such as the upregulation of profibrotic genes and epigenetic changes induced by hypoxia, capillary leakage, endothelial and pericyte transition to interstitial fibroblasts, as well as modifications in the secretome of endothelial cells. Alloimmune injury due to antibody-mediated rejection and ischemia-reperfusion injury are the two main etiologies of microvascular damage in kidney transplant recipients. The presence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies, histological findings, such as diffuse C4d staining in peritubular capillaries, and the extent and severity of peritubular capillaritis, are commonly used clinically to provide both diagnostic and prognostic information. Complement-dependent assays, circulating non-HLA antibodies, or evaluation of the microvasculature with novel imaging techniques are the subject of ongoing studies.
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Affiliation(s)
- Alice Doreille
- Research Centre, Centre Hospitalier de l'Université de Montréal , Montreal, Quebec , Canada.,Université Paris-Sud , Paris , France
| | - Mélanie Dieudé
- Research Centre, Centre Hospitalier de l'Université de Montréal , Montreal, Quebec , Canada.,Canadian Donation and Transplantation Research Program, Montreal, Quebec, Canada
| | - Heloise Cardinal
- Research Centre, Centre Hospitalier de l'Université de Montréal , Montreal, Quebec , Canada.,Canadian Donation and Transplantation Research Program, Montreal, Quebec, Canada
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37
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B Cell Activating Factor, Renal Allograft Antibody-Mediated Rejection, and Long-Term Outcome. J Immunol Res 2018; 2018:5251801. [PMID: 29977928 PMCID: PMC6011068 DOI: 10.1155/2018/5251801] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 03/07/2018] [Indexed: 12/16/2022] Open
Abstract
Antibody-mediated rejection (ABMR) of renal allograft lacks typical phenotypes and clinical manifestations, always resulting in delayed diagnosis and treatment. It has been considered to be an elemental factor influencing the improvement of the long-term outcome of renal allograft. The B cell activating factor (BAFF) signal plays a fundamental function in the process of antibody-mediated immune response. Data from recipients and the nonhuman primate ABMR model suggest that the BAFF signal participates in the ABMR of renal allograft, while there are objections. The challenges in the diagnosis of ABMR, different study population, and details of research may explain the discrepancy. Large quantities of dynamic, credible data of BAFF ligands and their association with renal allograft pathological characteristics would constitute a direct proof of the role of BAFF in the progression of renal allograft ABMR.
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38
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Aguilar PR, Carpenter D, Ritter J, Yusen RD, Witt CA, Byers DE, Mohanakumar T, Kreisel D, Trulock EP, Hachem RR. The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation. Am J Transplant 2018; 18:936-944. [PMID: 28992372 PMCID: PMC5878693 DOI: 10.1111/ajt.14534] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/10/2017] [Accepted: 09/29/2017] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single-center study to characterize cases of C4d-negative probable AMR and to compare these to cases of definite (C4d-positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d-positive and 45 (62%) were C4d-negative. The two groups had a similar clinical presentation, and although more patients in the C4d-positive group had neutrophilic capillaritis (54% vs. 29%, P = .035), there was no significant difference in the presence of other histologic findings. Despite aggressive antibody-depleting therapy, 19 of 73 (26%) patients in the overall cohort died within 30 days, but there was no significant difference in freedom from chronic lung allograft dysfunction (CLAD) or survival between the two groups. We conclude that AMR may cause allograft failure, but that the diagnosis requires a multidisciplinary approach and a high index of suspicion. C4d deposition does not appear to be a necessary criterion for the diagnosis, and although some cases may respond initially to therapy, there is a high incidence of CLAD and poor survival after AMR.
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Affiliation(s)
- PR Aguilar
- Baylor University Medical Center Division of Pulmonary & Critical Care, Dallas, TX
| | - D Carpenter
- St. Louis University School of Medicine Department of Pathology, St. Louis, MO
| | - J Ritter
- Washington University School of Medicine Department of Pathology & Immunology, St. Louis, MO
| | - RD Yusen
- Washington University School of Medicine Division of Pulmonary & Critical Care, St Louis, MO
| | - CA Witt
- Washington University School of Medicine Division of Pulmonary & Critical Care, St Louis, MO
| | - DE Byers
- Washington University School of Medicine Division of Pulmonary & Critical Care, St Louis, MO
| | | | - D Kreisel
- Washington University School of Medicine Division of Cardiothoracic Surgery, St. Louis, MO
| | - EP Trulock
- Washington University School of Medicine Division of Pulmonary & Critical Care, St Louis, MO
| | - RR Hachem
- Washington University School of Medicine Division of Pulmonary & Critical Care, St Louis, MO
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39
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Orandi BJ, Luo X, King EA, Garonzik-Wang JM, Bae S, Montgomery RA, Stegall MD, Jordan SC, Oberholzer J, Dunn TB, Ratner LE, Kapur S, Pelletier RP, Roberts JP, Melcher ML, Singh P, Sudan DL, Posner MP, El-Amm JM, Shapiro R, Cooper M, Lipkowitz GS, Rees MA, Marsh CL, Sankari BR, Gerber DA, Nelson PW, Wellen J, Bozorgzadeh A, Gaber AO, Segev DL. Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study. Am J Transplant 2018; 18:650-658. [PMID: 28834181 PMCID: PMC5820188 DOI: 10.1111/ajt.14472] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 08/06/2017] [Accepted: 08/11/2017] [Indexed: 01/25/2023]
Abstract
Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care.
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Affiliation(s)
- Babak J. Orandi
- Department of Surgery, University of California-San Francisco, San Francisco, CA
| | - Xun Luo
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Elizabeth A. King
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Sunjae Bae
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Robert A. Montgomery
- The NYU Transplant Institute, New York University Langone Medical Center, NY, NY
| | | | - Stanley C. Jordan
- Department of Medicine, Cedars-Sinai Comprehensive Transplant Center, Los Angeles, CA
| | - Jose Oberholzer
- Department of Surgery, University of Illinois-Chicago, Chicago IL
| | - Ty B. Dunn
- Department of Surgery, University of Minnesota, Minneapolis, MN
| | - Lloyd E. Ratner
- Department of Surgery, Columbia University Medical Center, New York, NY
| | - Sandip Kapur
- Department of Surgery, New York Presbyterian/Weill Cornell Medical Center, New York, NY
| | | | - John P. Roberts
- Department of Surgery, University of California-San Francisco, San Francisco, CA
| | | | - Pooja Singh
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA
| | - Debra L. Sudan
- Department of Surgery, Duke University Medical Center, Durham, NC
| | - Marc P. Posner
- Department of Surgery, Virginia Commonwealth University, Richmond, VA
| | - Jose M. El-Amm
- Integris Baptist Medical Center, Transplant Division, Oklahoma City, OK
| | - Ron Shapiro
- Recanati Miller Transplantation Institute, Mount Sinai Hospital, New York, NY
| | | | | | - Michael A. Rees
- Department of Urology, University of Toledo Medical Center, Toledo, OH
| | | | | | - David A. Gerber
- Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Paul W. Nelson
- Department of Surgery, University of Nevada, Las Vegas, NV
| | - Jason Wellen
- Department of Surgery, Barnes-Jewish Hospital, St. Louis, MO
| | - Adel Bozorgzadeh
- Department of Surgery, University of Massachusetts Memorial Medical Center, Worcester, MA
| | - A. Osama Gaber
- Department of Surgery, Houston Methodist Hospital, Houston, TX
| | - Dorry L. Segev
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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40
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Viglietti D, Loupy A, Aubert O, Bestard O, Duong Van Huyen JP, Taupin JL, Glotz D, Legendre C, Jouven X, Delahousse M, Kamar N, Lefaucheur C. Dynamic Prognostic Score to Predict Kidney Allograft Survival in Patients with Antibody-Mediated Rejection. J Am Soc Nephrol 2018; 29:606-619. [PMID: 29255058 PMCID: PMC5791064 DOI: 10.1681/asn.2017070749] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Accepted: 11/13/2017] [Indexed: 12/25/2022] Open
Abstract
No tool is available for the early assessment of response to antibody-mediated rejection (ABMR) therapies in kidney allograft recipients. This study was designed to define a dynamic composite prognostic ABMR score to predict kidney allograft survival, integrating the disease characteristics at diagnosis and the response to treatment. Among 1978 kidney recipients who underwent transplant between 2008 and 2014, we included 278 patients diagnosed with active ABMR and receiving standard treatment, including plasma exchange, intravenous Ig, and rituximab. Patients were prospectively assessed at diagnosis and after treatment for clinical data, histologic characteristics (allograft biopsy specimen), and donor-specific anti-HLA antibodies (DSA). The dynamic ABMR prediction model included GFR (P<0.001) and presence of interstitial fibrosis/tubular atrophy (P=0.003) at diagnosis and changes in GFR (P<0.001), peritubular capillaritis Banff score (P=0.002), and DSA mean fluorescence intensity (P<0.001) after treatment. Overall, this model showed good calibration and discrimination (C-statistic=0.84). The ABMR prognostic score derived from the prediction model identified three risk strata with 6-year kidney allograft survival rates of 6.0% (high-risk group, n=40), 44.9% (intermediate-risk group, n=36), and 84.4% (low-risk group, n=202), and it provided greater net clinical benefit to patients than did considering them all to have the same level of risk of allograft loss. The performance of the ABMR prognostic score was validated in an independent cohort of 202 kidney recipients with ABMR (C-statistic=0.79). The ABMR prognostic score could be used to inform therapeutic decisions in clinical practice and for the design of clinical trials.
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Affiliation(s)
- Denis Viglietti
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France
- Departments of Kidney Transplant and
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France;
- Departments of Kidney Transplant and
| | - Olivier Aubert
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France
| | - Oriol Bestard
- Department of Nephrology, Bellvitge University Hospital, Barcelona, Spain
| | - Jean-Paul Duong Van Huyen
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France
- Pathology, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Jean-Luc Taupin
- Immunology and Histocompatibility, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France
- Departments of Kidney Transplant and
| | - Christophe Legendre
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France
- Departments of Kidney Transplant and
| | - Xavier Jouven
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France
| | - Michel Delahousse
- Department of Nephrology and Kidney Transplantation, Foch Hospital, Suresnes, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, Centre Hospitalier Universtaire Rangueil, Toulouse; and
- Institut National de la Santé et de la Recherche Médicale U1043, IFR-BMT, Centre Hospitalier Universtaire Purpan, Toulouse, Université Paul Sabatier, Toulouse, France
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S970, Paris, France;
- Departments of Kidney Transplant and
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41
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Abstract
Donor-specific antibodies have become an established biomarker predicting antibody-mediated rejection. Antibody-mediated rejection is the leading cause of graft loss after kidney transplant. There are several phenotypes of antibody-mediated rejection along post-transplant course that are determined by the timing and extent of humoral response and the various characteristics of donor-specific antibodies, such as antigen classes, specificity, antibody strength, IgG subclasses, and complement binding capacity. Preformed donor-specific antibodies in sensitized patients can trigger hyperacute rejection, accelerated acute rejection, and early acute antibody-mediated rejection. De novo donor-specific antibodies are associated with late acute antibody-mediated rejection, chronic antibody-mediated rejection, and transplant glomerulopathy. The pathogeneses of antibody-mediated rejection include not only complement-dependent cytotoxicity, but also complement-independent pathways of antibody-mediated cellular cytotoxicity and direct endothelial activation and proliferation. The novel assay for complement binding capacity has improved our ability to predict antibody-mediated rejection phenotypes. C1q binding donor-specific antibodies are closely associated with acute antibody-mediated rejection, more severe graft injuries, and early graft failure, whereas C1q nonbinding donor-specific antibodies correlate with subclinical or chronic antibody-mediated rejection and late graft loss. IgG subclasses have various abilities to activate complement and recruit effector cells through the Fc receptor. Complement binding IgG3 donor-specific antibodies are frequently associated with acute antibody-mediated rejection and severe graft injury, whereas noncomplement binding IgG4 donor-specific antibodies are more correlated with subclinical or chronic antibody-mediated rejection and transplant glomerulopathy. Our in-depth knowledge of complex characteristics of donor-specific antibodies can stratify the patient's immunologic risk, can predict distinct phenotypes of antibody-mediated rejection, and hopefully, will guide our clinical practice to improve the transplant outcomes.
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Affiliation(s)
- Rubin Zhang
- Section of Nephrology, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana
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42
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Montgomery RA, Loupy A, Segev DL. Antibody-mediated rejection: New approaches in prevention and management. Am J Transplant 2018; 18 Suppl 3:3-17. [PMID: 29292861 DOI: 10.1111/ajt.14584] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 10/26/2017] [Accepted: 11/04/2017] [Indexed: 01/25/2023]
Abstract
Despite the success of desensitization protocols, antibody-mediated rejection (AMR) remains a significant contributor to renal allograft failure in patients with donor-specific antibodies. Plasmapheresis and high-dose intravenous immunoglobulin have proved to be effective treatments to prevent and treat AMR, but irreversible injury in the form of transplant glomerulopathy can commonly manifest months to years later. There is an unmet need to improve the outcomes for patients at risk for AMR. Updated Banff criteria now take into account the increasing understanding of the complex and heterogeneous nature of AMR phenotypes, including the timing of rejection, subclinical and chronic AMR, C4d-negative AMR, and antibody-mediated vascular rejection. Treatment for AMR is not standardized, and there is little in the way of evidence-based treatment guidelines. Refining more precisely the mechanisms of injury responsible for different AMR phenotypes and establishing relevant surrogate endpoints to facilitate more informative studies will likely allow for more accurate determination of prognosis and efficacious intervention using new therapeutic approaches. In addition to plasma exchange and intravenous immunoglobulin, a number of other add-on therapies have been tried in small studies without consistent benefit, including anti-CD20, proteasome inhibitors, complement inhibitors, anti-interleukin-6 receptor blockers, and immunoglobulin G-degrading enzyme of Streptococcus pyogenes (called IdeS).
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Affiliation(s)
- R A Montgomery
- Department of Surgery and NYU Langone Transplant Institute, NYU Langone Medical Center, New York, NY, USA
| | - A Loupy
- Paris Translational Research Center for Organ Transplantation and Department of Nephrology and Kidney Transplantation, Hôpital Necker, INSERM U 970, Paris Descartes University, Paris, France
| | - D L Segev
- Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
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43
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Abstract
Despite advances in immunosuppression over the past 25 years, acute cellular rejection remains a common complication early after lung transplantation. Although acute cellular rejection has often not resulted in clinical signs or symptoms of allograft dysfunction, it has been widely recognized as a strong independent risk factor for the development of chronic rejection, emphasizing its clinical significance. In recent years, the role of humoral immunity in lung rejection has been increasingly appreciated, and antibody-mediated rejection is now recognized as a form of rejection that may result in allograft failure.
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Affiliation(s)
- Ramsey R Hachem
- Division of Pulmonary and Critical Care, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8052, St Louis, MO 63110, USA.
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44
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Moktefi A, Parisot J, Desvaux D, Canoui-Poitrine F, Brocheriou I, Peltier J, Audard V, Kofman T, Suberbielle C, Lang P, Rondeau E, Grimbert P, Matignon M. C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody-mediated rejection episode: a retrospective cohort study. Transpl Int 2017; 30:277-287. [PMID: 27992962 DOI: 10.1111/tri.12905] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/03/2016] [Accepted: 12/12/2016] [Indexed: 11/30/2022]
Abstract
After kidney transplantation, C4d is an incomplete marker of acute antibody-mediated rejection (AMR) and C1q-binding donor-specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q-binding impact on allograft survival. We compared clinical, histological and serological features of C4d- and C4d+ AMR, C1q+ and C1q- DSA AMR and analysed C4d and C1q-binding impact on allograft survival. Among 500 for-cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.11-6.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q- AMR.
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Affiliation(s)
- Anissa Moktefi
- APHP (Assistance Publique-Hôpitaux de Paris), Pathology Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France.,DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, Université Paris-Est-Créteil (UPEC), Créteil, France
| | - Juliette Parisot
- AP-HP (Assistance Publique-Hôpitaux de Paris), Public Health Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France
| | - Dominique Desvaux
- APHP (Assistance Publique-Hôpitaux de Paris), Pathology Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France.,DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, Université Paris-Est-Créteil (UPEC), Créteil, France
| | - Florence Canoui-Poitrine
- AP-HP (Assistance Publique-Hôpitaux de Paris), Public Health Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France.,DHU (Département Hositalo-Universitaire) A-TVB, IMRB (Institut Mondor de Recherche Biomédicale)- EA 7376 CEpiA (Clinical Epidemiology And Ageing Unit), Université Paris-Est-Créteil, UPEC, Créteil, France
| | - Isabelle Brocheriou
- AP-HP (Assistance Publique-Hôpitaux de Paris), Pathology Department, Tenon Hospital, Paris, France.,INSERM UMRS_1155, Université Pierre et Marie Curie, Paris, France
| | - Julie Peltier
- INSERM UMRS_1155, Université Pierre et Marie Curie, Paris, France.,AP-HP (Assistance Publique-Hôpitaux de Paris), Intensive Care Nephrology and Renal Transplantation, Tenon Hospital, Paris, France
| | - Vincent Audard
- DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, Université Paris-Est-Créteil (UPEC), Créteil, France.,AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France
| | - Tomek Kofman
- AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France
| | - Caroline Suberbielle
- AP-HP (Assistance Publique-Hôpitaux de Paris), Immunology and Histocompatibility Department, Saint Louis Hospital, Paris, France
| | - Philippe Lang
- DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, Université Paris-Est-Créteil (UPEC), Créteil, France.,AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France
| | - Eric Rondeau
- INSERM UMRS_1155, Université Pierre et Marie Curie, Paris, France.,AP-HP (Assistance Publique-Hôpitaux de Paris), Intensive Care Nephrology and Renal Transplantation, Tenon Hospital, Paris, France
| | - Philippe Grimbert
- DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, Université Paris-Est-Créteil (UPEC), Créteil, France.,AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France.,AP-HP, CIC-BT 504, Créteil, France
| | - Marie Matignon
- DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, Université Paris-Est-Créteil (UPEC), Créteil, France.,AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation (IFRNT), Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France.,AP-HP, CIC-BT 504, Créteil, France
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45
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Sullivan HC, Gebel HM, Bray RA. Understanding solid-phase HLA antibody assays and the value of MFI. Hum Immunol 2017; 78:471-480. [DOI: 10.1016/j.humimm.2017.05.007] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Revised: 05/26/2017] [Accepted: 05/29/2017] [Indexed: 01/10/2023]
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46
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Valenzuela NM, Reed EF. Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies. J Clin Invest 2017; 127:2492-2504. [PMID: 28604384 DOI: 10.1172/jci90597] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.
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47
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Human Pooled Immunoglobulin as Treatment of Active Antibody-Mediated Rejection of Transplanted Kidney. Transplant Proc 2017; 48:1446-50. [PMID: 27496425 DOI: 10.1016/j.transproceed.2016.02.054] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Revised: 01/30/2016] [Accepted: 02/24/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND Antibody-mediated rejection (ABMR) has emerged as the leading cause of renal graft loss. The optimal treatment protocol in ABMR remains unknown. This study aimed to assess the efficacy of intravenous immunoglobulin (IVIG) for treatment of ABMR in renal recipients. METHODS Thirty-nine ABO-compatible cross-match-negative renal recipients with biopsy-proven ABMR composed the study group. Pulses of methylprednisolone (MP) and appropriate enhancement of net state of immunosuppression were applied in all individuals; 17/39 recipients were administered IVIG (IVIG group); the remaining 22/39 patients, identified to be nonadherent or unsatisfactorily immunosuppressed, were kept on the initial treatment (MP group). Serum creatinine concentration was obtained at each of 10 intended visits, and glomerular filtration rate (GFR) was estimated with the use of the standard Modification of Diet in Renal Disease (MDRD) formula. Generalized linear mixed model was used for statistical analysis. RESULTS Renal function (modeled as linear slope of MDRD-based GFR change over time, separately for the pre- and post-intervention periods) improved significantly in IVIG-treated recipients. Pre-intervention slopes were -0.72 and -0.46 mL/min/mo for IVIG and MP groups, respectively (P = NS), whereas post-intervention the slopes changed to -0.03 and -0.47 mL/min/mo (IVIG and MP, respectively; P < .005). Within-group changes of slopes at the time of intervention were 0.69 and -0.01 mL/min/mo in IVIG (P < .01) and MP (P = NS) groups, respectively. The relative slope change (pre- to post-intervention) was 0.7 mL/min/mo in favor of the IVIG group (P < .033). None of the classic immunologic or nonimmunologic graft function predictors influenced GFR during 12 months of follow-up. CONCLUSIONS IVIG improved graft function in renal recipients diagnosed with ABMR.
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48
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Haas M, Mirocha J, Reinsmoen NL, Vo AA, Choi J, Kahwaji JM, Peng A, Villicana R, Jordan SC. Differences in pathologic features and graft outcomes in antibody-mediated rejection of renal allografts due to persistent/recurrent versus de novo donor-specific antibodies. Kidney Int 2017; 91:729-737. [DOI: 10.1016/j.kint.2016.10.040] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/06/2016] [Accepted: 10/27/2016] [Indexed: 10/20/2022]
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49
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Menon MC, Murphy B, Heeger PS. Moving Biomarkers toward Clinical Implementation in Kidney Transplantation. J Am Soc Nephrol 2017; 28:735-747. [PMID: 28062570 DOI: 10.1681/asn.2016080858] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Long-term kidney transplant outcomes remain suboptimal, delineating an unmet medical need. Although current immunosuppressive therapy in kidney transplant recipients is effective, dosing is conventionally adjusted empirically on the basis of time after transplant or altered in response to detection of kidney dysfunction, histologic evidence of allograft damage, or infection. Such strategies tend to detect allograft rejection after significant injury has already occurred, fail to detect chronic subclinical inflammation that can negatively affect graft survival, and ignore specific risks and immune mechanisms that differentially contribute to allograft damage among transplant recipients. Assays and biomarkers that reliably quantify and/or predict the risk of allograft injury have the potential to overcome these deficits and thereby, aid clinicians in optimizing immunosuppressive regimens. Herein, we review the data on candidate biomarkers that we contend have the highest potential to become clinically useful surrogates in kidney transplant recipients, including functional T cell assays, urinary gene and protein assays, peripheral blood cell gene expression profiles, and allograft gene expression profiles. We identify barriers to clinical biomarker adoption in the transplant field and suggest strategies for moving biomarker-based individualization of transplant care from a research hypothesis to clinical implementation.
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Affiliation(s)
- Madhav C Menon
- Renal Division, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Barbara Murphy
- Renal Division, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Peter S Heeger
- Renal Division, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
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50
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Desensitization: Overcoming the Immunologic Barriers to Transplantation. J Immunol Res 2017; 2017:6804678. [PMID: 28127571 PMCID: PMC5239985 DOI: 10.1155/2017/6804678] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/14/2016] [Indexed: 12/17/2022] Open
Abstract
HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection.
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