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Mitomo A, Tanabe K, Muraoka S, Yanai M, Hidaka S, Kobayashi S. Prophylactic use of eculizumab for ABO-blood type incompatible kidney transplantation with extremely high ABO-blood type antibody titer: A two case report. Transpl Immunol 2025; 90:102213. [PMID: 40024311 DOI: 10.1016/j.trim.2025.102213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 02/25/2025] [Accepted: 02/27/2025] [Indexed: 03/04/2025]
Abstract
We report two cases of ABO-incompatible living-donor kidney transplantation (ABOi KT) performed in patients with exceptionally high ABO antibody titers. Both donor and recipient refused blood transfusions for religious reasons, limiting the use of plasma exchange. The desensitization protocol consisted of plasmapheresis (PP) using albumin solution, rituximab (300 mg), and high-dose intravenous immunoglobulin (IVIg; 4 g/kg). Despite aggressive desensitization procedure, ABO antibody titers did not go down to our acceptable upper limit of 1:64; the titer at transplantation was 1:256 in both cases. Given the high risk of acute antibody-mediated rejection (ABMR), the anti-complement C5 component monoclonal antibody (eculizumab; 900 mg) was administered prophylactically before graft reperfusion in order to inhibit complement activation. For both cases, postoperative courses were unremarkable, without any rejection episodes over one year. No additional doses of eculizumab were administered post-transplantation. We suggest that ABOi KT may be considered safe once early post-transplant ABMR is suppressed, allowing for immunological accommodation. Furthermore, despite the elevated antibody titers, the prophylaxis with eculizumab successfully inhibited early post-transplant complement activation, protecting kidney transplants from ABMR. These findings support the prophylactic use of eculizumab administration at the time of transplantation in high-risk cases of ABOi KT.
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Affiliation(s)
- Ayaka Mitomo
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan
| | - Kazunari Tanabe
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan.
| | - Suguru Muraoka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan
| | - Mitsuru Yanai
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan; Department of Diagnostic Pathology, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan
| | - Sumi Hidaka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan
| | - Shuzo Kobayashi
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1370-1 Okamoto, 247-8533 Kamakura, Kanagawa, Japan
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2
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Bertrand D, Del Bello A, Sberro Soussan R, Caillard S, Claisse G, Couzi L, Girerd S, Hertig A, Le Meur Y, Pernin V, Poulain C, Rafat C, Matignon M, Buteux A, François A, Lemoine M, Laurent C, Kamar N, de Nattes T, Guerrot D. Early Thrombotic Microangiopathy After ABO-Incompatible Living Donor Kidney Transplantation. Kidney Int Rep 2025; 10:828-837. [PMID: 40225375 PMCID: PMC11993204 DOI: 10.1016/j.ekir.2024.12.031] [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: 09/20/2024] [Revised: 12/11/2024] [Accepted: 12/23/2024] [Indexed: 04/15/2025] Open
Abstract
Introduction Although long-term graft survival is comparable with that of ABO-compatible (ABOc) renal transplantation, the risk of antibody-mediated rejection (ABMR) following ABO-incompatible (ABOi) transplantation is higher and can occur as an early thrombotic microangiopathy (TMA). Methods We designed a retrospective multicenter study, including all patients who presented with a TMA (histological and/or biological) after an ABOi transplantation (< 1 month) and compared with matched controls who had a favorable initial course with a normal biopsy. Results Between 2013 and 2022, 375 ABOi kidney transplants were performed and 23 patients (6.1%) developed TMA (median: 1 day, interquartile range [IQR]: 0-3 days). Twenty-one patients (91.3%) had biological TMA. Among 23 early graft biopsies, histological evidence of active TMA was found in 17 cases (80.9%). All patients received treatment: 20 of 23 received at least 1 session of plasmapheresis and 19 of 23 received at least 1 injection of eculizumab. Eight early graft losses (30.4%) occurred (median: 7 days, IQR: 3-16 days). IgG and IgM anti-blood group antibody (ABGA) levels (peak and last pregraft assay) were significantly higher in the TMA group (peak: P = 0.01 for IgG and P = 0.0006 for IgM; last assay before kidney transplantation [KT]: P < 0.0001 for IgG and P = 0.0003 for IgM). A level ≥ 1/8 for IgG and ≥ 1/4 or IgM before transplantation were significantly and independently predictive of the occurrence of TMA. No other predictive factors were found. Conclusion TMA after ABOi transplantation is not a rare phenomenon and is associated with a poor prognosis in nonresponders-to-treatment patients. ABGA titer performed by hemagglutination is an imperfect marker of the occurrence of such a phenomenon.
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Affiliation(s)
- Dominique Bertrand
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Arnaud Del Bello
- Nephrology and Organ Transplantation Department, Rangueil Toulouse University Hospital, Toulouse, France
| | - Rebecca Sberro Soussan
- Necker-Enfants Malades Institute, French National Institute of Health and Medical Research, Paris, France
| | - Sophie Caillard
- Nephrology and Transplantation Department, Strasbourg University Hospital, Strasbourg, France
| | - Guillaume Claisse
- Nephrology, Dialysis and Renal Transplantation Department, Hôpital Nord, CHU de Saint-Etienne, Jean Monnet University, Université de Lyon, Saint-Etienne, France
| | - Lionel Couzi
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Bordeaux University Hospital, Rouen, France
| | - Sophie Girerd
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Nancy University Hospital, Rouen, France
| | - Alexandre Hertig
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Foch Hospital, Suresnes, France
| | - Yannick Le Meur
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Brest University Hospital, Rouen, France
| | - Vincent Pernin
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Montpellier University Hospital, Rouen, France
| | - Coralie Poulain
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Amiens University Hospital, Rouen, France
| | - Cédric Rafat
- Soins Intensifs de Néphrologie et Rein Aigu, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Marie Matignon
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Arnaud Buteux
- EFS Etablissement Français du Sang, Rouen University Hospital, Rouen, France
| | - Arnaud François
- Service d'anatomopathologie, Rouen University Hospital, Rouen, France
| | - Mathilde Lemoine
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Charlotte Laurent
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Nassim Kamar
- Nephrology and Organ Transplantation Department, Rangueil Toulouse University Hospital, Toulouse, France
| | - Tristan de Nattes
- Department of Nephrology, INSERM U1234, CHU Rouen, Nephrology Department, Universite Rouen Normandie, Rouen, France
| | - Dominique Guerrot
- Department of Nephrology, INSERM U1096, CHU Rouen, Universite Rouen Normandie, Rouen, France
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3
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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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Lokkur P, Bansal SB. Complement in Kidney Transplantation. Transplant Rev (Orlando) 2025; 39:100897. [PMID: 39615219 DOI: 10.1016/j.trre.2024.100897] [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: 09/04/2024] [Revised: 11/13/2024] [Accepted: 11/22/2024] [Indexed: 01/11/2025]
Abstract
Transplantation is the treatment of choice in most patients with kidney failure. The complement system plays a vital role in transplantation. The complement system forms a major part of innate immunity and acts as a bridge between innate and acquired immunity. Many diseases, particularly concerning the kidneys, result from complement system dysregulation, like atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3GN), systemic lupus erythematosus (SLE and some other immune complex diseases. The complement system activation is a very important part of post-transplant events like ischemia-reperfusion injury (IRI), delayed graft function (DGF), antibody-mediated rejection (ABMR) and thrombotic microangiopathy (TMA). A better understanding of the complement cascade can help to plan strategies to prevent and manage complement-related problems before and after kidney transplantation. Many newer molecules are either being developed or in the pipeline, which target the complement system at various stages. These novel therapeutics are now considered additional measures to improve graft survival. This review summarises the complement cascade, its role in kidney diseases and kidney transplantation, and possible areas of target and novel therapeutics.
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Affiliation(s)
- Pooja Lokkur
- Department of Nephrology and Kidney Transplantation, Medanta Medicity, Sector 38, Gurgaon 122001, India
| | - Shyam Bihari Bansal
- Department of Nephrology and Kidney Transplantation, Medanta Medicity, Sector 38, Gurgaon 122001, India.
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Heo GY, Jung M, Piao H, Kim HJ, Kim HW, Lee J, Huh KH, Kim BS, Yang J. Successful eculizumab treatment as an adjunctive therapy to desensitization in ABO-incompatible living donor kidney transplantation and its molecular phenotypes. Front Immunol 2024; 15:1465851. [PMID: 39530089 PMCID: PMC11550984 DOI: 10.3389/fimmu.2024.1465851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction ABO-incompatible (ABOi) kidney transplantation (KT) has become an important option to overcome organ shortage. Plasmapheresis/rituximab-based desensitization therapy has successfully reduced anti-ABO antibody levels and suppressed antibody-mediated rejection (AMR) in ABOi KT. However, high titers of anti-ABO antibodies in some patients are refractory to standard desensitization, leading to loss of KT opportunities or AMR. Methods Eculizumab treatment was used an adjunctive therapy to rescue high-titer ABOi KT patients refractory to plasmapheresis/rituximab-based desensitization. Molecular phenotypes of allograft biopsies and cellular phenotypes of peripheral blood mononuclear cells of eculizumab group were compared with those of control groups using the Banff Human Organ Transplant gene panel and flow-cytometric analysis, respectively. Results The initial titers of anti-ABO antibodies in the two patients were 1:512 and >1:1024; the final pre-transplant titers after desensitization were 1:128 and 1:64. Both patients received eculizumab from KT day to two or four weeks post-KT and maintained stable renal function up to one-year post-transplantation without overt infection, despite early episodes of probable AMR or borderline T cell-mediated rejection. Molecular phenotype analysis revealed that gene expression patterns in the ABOi KT with eculizumab group overlapped with those in the ABOi KT with AMR group more than in the ABOi KT without AMR group, except for complement pathway-related gene expression. Anti-ABO antibody titers decreased to low levels 1-3 months post-transplant in the eculizumab group in parallel with decreasing anti-B-specific B cells. Conclusions Short-term eculizumab therapy is promising for rescuing ABOi KT recipients with high anti-ABO antibody titers refractory to plasmapheresis-based desensitization therapy.
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Affiliation(s)
- Ga Young Heo
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Minsun Jung
- Department of Pathology, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Honglin Piao
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Hyun Jeong Kim
- Department of Surgery, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Hyung Woo Kim
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Juhan Lee
- Department of Surgery, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Kyu Ha Huh
- Department of Surgery, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Beom Seok Kim
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Jaeseok Yang
- Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
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6
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Iesari S, Nava FL, Zais IE, Coubeau L, Ferraresso M, Favi E, Lerut J. Advancing immunosuppression in liver transplantation: A narrative review. Hepatobiliary Pancreat Dis Int 2024; 23:441-448. [PMID: 38523030 DOI: 10.1016/j.hbpd.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 03/14/2024] [Indexed: 03/26/2024]
Abstract
Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.
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Affiliation(s)
- Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Francesca Laura Nava
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Ilaria Elena Zais
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy
| | - Laurent Coubeau
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium; Service de Chirurgie et Transplantation Abdominale, Cliniques Universitaires Saint-Luc, 55 Avenue Hippocrate, 1200 Brussels, Belgium
| | - Mariano Ferraresso
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy
| | - Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 15 Via della Commenda, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 19 Via della Commenda, 20122 Milan, Italy.
| | - Jan Lerut
- Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, 10 Avenue Hippocrate, 1200 Brussels, Belgium
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Kleiboeker HL, Prom A, Paplaczyk K, Myers CN. A Complement to Traditional Treatments for Antibody-Mediated Rejection? Use of Eculizumab in Lung Transplantation: A Review and Early Center Experience. Ann Pharmacother 2024; 58:947-955. [PMID: 37994573 DOI: 10.1177/10600280231213112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2023] Open
Abstract
OBJECTIVE To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs). DATA SOURCES A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant, and AMR. STUDY SELECTION AND DATA EXTRACTION All relevant English-language studies were reviewed and considered. DATA SYNTHESIS Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function. CONCLUSIONS Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival.
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Affiliation(s)
- Hanna L Kleiboeker
- Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Alyson Prom
- Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Krista Paplaczyk
- Department of Pharmacy, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Catherine N Myers
- Division of Pulmonary and Critical Care, Department of Medicine, Northwestern Memorial Hospital, Chicago, IL, USA
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Favi E, Cresseri D, Perego M, Ikehata M, Iesari S, Campise MR, Morello W, Testa S, Sioli V, Mattinzoli D, Longhi E, Del Gobbo A, Castellano G, Ferraresso M. Sequential administration of anti-complement component C5 eculizumab and type-2 anti-CD20 obinutuzumab for the treatment of early antibody-mediated rejection after kidney transplantation: A proof of concept. Clin Immunol 2024; 264:110240. [PMID: 38734036 DOI: 10.1016/j.clim.2024.110240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 04/02/2024] [Accepted: 05/08/2024] [Indexed: 05/13/2024]
Abstract
Kidney transplant (KT) candidates with donor-specific antibodies (DSA) exhibit exceedingly high antibody-mediated rejection (ABMR) and allograft loss rates. Currently, treatment of ABMR remains an unmet clinical need. We report the use of the anti-C5 eculizumab and the type-2 anti-CD20 obinutuzumab in two patients with early ABMR. Eculizumab (900 mg IV) led to complete inhibition of the terminal complement cascade (unremarkable AP50 and CH50 activity) and prompt stoppage of complement-dependent antibody-mediated allograft injury (clearance of intra-graft C4d and C5b-9 deposition). Despite complement inhibition, obinutuzumab (1000 mg IV) determined full and long-lasting peripheral B-cell depletion, with significant reduction in all DSA. Graft function improved, remaining stable up to three years of follow-up. No signs of active ABMR and rebound DSA were detected. Obinutuzumab B-cell depletion and inhibition of DSA production were not affected by complement blockage. Further studies are needed to confirm the potential benefit of obinutuzumab in association with complement inhibitors.
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Affiliation(s)
- Evaldo Favi
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy.
| | - Donata Cresseri
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Marta Perego
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Masami Ikehata
- Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Samuele Iesari
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Maria Rosaria Campise
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - William Morello
- Pediatric Nephrology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Sara Testa
- Pediatric Nephrology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Viviana Sioli
- Laboratorio di Immunologia dei Trapianti, Trapianti Lombardia - NITp, 20122 Milan, Italy
| | - Deborah Mattinzoli
- Renal Research Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Elena Longhi
- Laboratorio di Immunologia dei Trapianti, Trapianti Lombardia - NITp, 20122 Milan, Italy
| | - Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Giuseppe Castellano
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy; Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Mariano Ferraresso
- General Surgery and Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
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9
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Furian L, Bestard O, Budde K, Cozzi E, Diekmann F, Mamode N, Naesens M, Pengel LHM, Schwartz Sorensen S, Vistoli F, Thaunat O. European Consensus on the Management of Sensitized Kidney Transplant Recipients: A Delphi Study. Transpl Int 2024; 37:12475. [PMID: 38665475 PMCID: PMC11043529 DOI: 10.3389/ti.2024.12475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/04/2024] [Indexed: 04/28/2024]
Abstract
An increasing number of sensitized patients awaiting transplantation face limited options, leading to fatalities during dialysis and higher costs. The absence of established evidence highlights the need for collaborative consensus. Donor-specific antibodies (DSA)-triggered antibody-mediated rejection (AMR) significantly contributes to kidney graft failure, especially in sensitized patients. The European Society for Organ Transplantation (ESOT) launched the ENGAGE initiative, categorizing sensitized candidates by AMR risk to improve patient care. A systematic review assessed induction and maintenance regimens as well as antibody removal strategies, with statements subjected to the Delphi methodology. A Likert-scale survey was distributed to 53 European experts (Nephrologists, Transplant surgeons and Immunologists) with experience in kidney transplant recipient care. A rate ≥75% with the same answer was considered consensus. Consensus was achieved in 95.3% of statements. While most recommendations aligned, two statements related to complement inhibitors for AMR prophylaxis lacked consensus. The ENGAGE consensus presents contemporary recommendations for desensitization and immunomodulation strategies, grounded in predefined risk categories. The adoption of tailored, patient-specific measures is anticipated to streamline the care of sensitized recipients undergoing renal allografts. While this approach holds the promise of enhancing transplant accessibility and fostering long-term success in transplantation outcomes, its efficacy will need to be assessed through dedicated studies.
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Affiliation(s)
- Lucrezia Furian
- Kidney and Pancreas Transplantation Unit, Department of Surgical, Oncological and Gastroenterological Sciences, School of Medicine and Surgery, University of Padua, Padua, Italy
| | - Oriol Bestard
- Kidney Transplant Unit, Vall d’Hebron University Hospital, Barcelona, Spain
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité University Medicine Berlin, Berlin, Germany
| | - Emanuele Cozzi
- Transplant Immunology Unit, Department of Cardiac, Thoracic and Vascular Sciences, School of Medicine and Surgery, University of Padua, Padua, Italy
| | - Fritz Diekmann
- Experimental Nephrology and Transplant Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
| | | | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, Faculty of Medicine, KU Leuven, Leuven, Belgium
- Erasmus MC Transplant Institute, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Liset H. M. Pengel
- Erasmus MC Transplant Institute, Erasmus University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Soren Schwartz Sorensen
- Department of Neurology, Rigshospitalet, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Fabio Vistoli
- University of Pisa, Pisa, Italy
- Department of Biothecnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Olivier Thaunat
- Service de Transplantation, Néphrologie et Immunologie Clinique, Hospices Civils de Lyon, Lyon, France
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10
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Luo Y, Wu X, Cai Z, Liu F, Li L, Tu Y. The Effect of Splenic Irradiation on Mean Fluorescence Intensity Values of HLA Antibody in Presensitized Patients Waiting for Kidney Transplantation. Transplant Proc 2023; 55:2362-2371. [PMID: 37891022 DOI: 10.1016/j.transproceed.2023.09.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 08/21/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023]
Abstract
To explore the desensitization treatment of patients waiting for kidney transplantation, this article comparative analysis of the effect of splenic irradiation on mean fluorescence intensity (MFI) values of HLA antibodies of 4 presensitized patients. After splenic irradiation, the mean MFI values of HLA-I antibody in 4 patients all decreased (P ≤ .001, P ≤ .001, P ≤ .001, P ≤ .001), and 3 patients had a decrease in intensity level (P ≤ .001, P = .001, P ≤ .001); as for HLA-II antibody, the mean MFI values in 3 patients also decreased (P ≤ .001, P = .025, P = .016), 1 patient had a decrease in intensity level (P ≤ .001) and the other 2 cases had no significant changes (P = 1.000, P = .564). On the other hand, splenic irradiation reduces MFI values in different levels of HLA antibody. So, splenic irradiation can reduce the MFI values of HLA antibodies.
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Affiliation(s)
- Yu Luo
- Department of Urology, Wuhan Sixth Hospital Affiliated Hospital of Jianghan University, Wuhan, China; Department of Nephropathy & Dialysis & Kidney Transplantation, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Xiongfei Wu
- Department of Nephropathy & Dialysis & Kidney Transplantation, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Zhitao Cai
- Department of Nephropathy & Dialysis & Kidney Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
| | - Feng Liu
- Department of Urology, Wuhan Sixth Hospital Affiliated Hospital of Jianghan University, Wuhan, China; Department of Nephropathy & Dialysis & Kidney Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lian Li
- Department of Nephropathy & Dialysis & Kidney Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yafang Tu
- Department of Nephropathy & Dialysis & Kidney Transplantation, Renmin Hospital of Wuhan University, Wuhan, China
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11
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Golshayan D, Schwotzer N, Fakhouri F, Zuber J. Targeting the Complement Pathway in Kidney Transplantation. J Am Soc Nephrol 2023; 34:1776-1792. [PMID: 37439664 PMCID: PMC10631604 DOI: 10.1681/asn.0000000000000192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 07/02/2023] [Indexed: 07/14/2023] Open
Abstract
The complement system is paramount in the clearance of pathogens and cell debris, yet is increasingly recognized as a key component in several pathways leading to allograft injury. There is thus a growing interest in new biomarkers to assess complement activation and guide tailored therapies after kidney transplantation (KTx). C5 blockade has revolutionized post-transplant management of atypical hemolytic uremic syndrome, a paradigm of complement-driven disease. Similarly, new drugs targeting the complement amplification loop hold much promise in the treatment and prevention of recurrence of C3 glomerulopathy. Although unduly activation of the complement pathway has been described after brain death and ischemia reperfusion, any clinical attempts to mitigate the ensuing renal insults have so far provided mixed results. However, the intervention timing, strategy, and type of complement blocker need to be optimized in these settings. Furthermore, the fast-moving field of ex vivo organ perfusion technology opens new avenues to deliver complement-targeted drugs to kidney allografts with limited iatrogenic risks. Complement plays also a key role in the pathogenesis of donor-specific ABO- and HLA-targeted alloantibodies. However, C5 blockade failed overall to improve outcomes in highly sensitized patients and prevent the progression to chronic antibody-mediated rejection (ABMR). Similarly, well-conducted studies with C1 inhibitors in sensitized recipients yielded disappointing results so far, in part, because of subtherapeutic dosage used in clinical studies. The emergence of new complement blockers raises hope to significantly reduce the negative effect of ischemia reperfusion, ABMR, and nephropathy recurrence on outcomes after KTx.
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Affiliation(s)
- Dela Golshayan
- Transplantation Center, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Nora Schwotzer
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Fadi Fakhouri
- Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Julien Zuber
- Service de Transplantation rénale adulte, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, Paris, France
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12
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Habibabady Z, McGrath G, Kinoshita K, Maenaka A, Ikechukwu I, Elias GF, Zaletel T, Rosales I, Hara H, Pierson RN, Cooper DKC. Antibody-mediated rejection in xenotransplantation: Can it be prevented or reversed? Xenotransplantation 2023; 30:e12816. [PMID: 37548030 PMCID: PMC11101061 DOI: 10.1111/xen.12816] [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: 06/17/2023] [Revised: 07/19/2023] [Accepted: 07/26/2023] [Indexed: 08/08/2023]
Abstract
Antibody-mediated rejection (AMR) is the commonest cause of failure of a pig graft after transplantation into an immunosuppressed nonhuman primate (NHP). The incidence of AMR compared to acute cellular rejection is much higher in xenotransplantation (46% vs. 7%) than in allotransplantation (3% vs. 63%) in NHPs. Although AMR in an allograft can often be reversed, to our knowledge there is no report of its successful reversal in a pig xenograft. As there is less experience in preventing or reversing AMR in models of xenotransplantation, the results of studies in patients with allografts provide more information. These include (i) depletion or neutralization of serum anti-donor antibodies, (ii) inhibition of complement activation, (iii) therapies targeting B or plasma cells, and (iv) anti-inflammatory therapy. Depletion or neutralization of anti-pig antibody, for example, by plasmapheresis, is effective in depleting antibodies, but they recover within days. IgG-degrading enzymes do not deplete IgM. Despite the expression of human complement-regulatory proteins on the pig graft, inhibition of systemic complement activation may be necessary, particularly if AMR is to be reversed. Potential therapies include (i) inhibition of complement activation (e.g., by IVIg, C1 INH, or an anti-C5 antibody), but some complement inhibitors are not effective in NHPs, for example, eculizumab. Possible B cell-targeted therapies include (i) B cell depletion, (ii) plasma cell depletion, (iii) modulation of B cell activation, and (iv) enhancing the generation of regulatory B and/or T cells. Among anti-inflammatory agents, anti-IL6R mAb and TNF blockers are increasingly being tested in xenotransplantation models, but with no definitive evidence that they reverse AMR. Increasing attention should be directed toward testing combinations of the above therapies. We suggest that treatment with a systemic complement inhibitor is likely to be most effective, possibly combined with anti-inflammatory agents (if these are not already being administered). Ultimately, it may require further genetic engineering of the organ-source pig to resolve the problem entirely, for example, knockout or knockdown of SLA, and/or expression of PD-L1, HLA E, and/or HLA-G.
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Affiliation(s)
- Zahra Habibabady
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Gannon McGrath
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Kohei Kinoshita
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Akihiro Maenaka
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Ileka Ikechukwu
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Gabriela F. Elias
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Tjasa Zaletel
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Ivy Rosales
- Department of Pathology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - Hidetaka Hara
- Yunnan Xenotransplantation Engineering Research Center, Yunnan Agricultural University, Kunming, Yunnan, China
| | - Richard N. Pierson
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
| | - David K. C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
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13
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Couzi L, Malvezzi P, Amrouche L, Anglicheau D, Blancho G, Caillard S, Freist M, Guidicelli GL, Kamar N, Lefaucheur C, Mariat C, Koenig A, Noble J, Thaunat O, Thierry A, Taupin JL, Bertrand D. Imlifidase for Kidney Transplantation of Highly Sensitized Patients With a Positive Crossmatch: The French Consensus Guidelines. Transpl Int 2023; 36:11244. [PMID: 37448448 PMCID: PMC10336835 DOI: 10.3389/ti.2023.11244] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/02/2023] [Indexed: 07/15/2023]
Abstract
Imlifidase recently received early access authorization for highly sensitized adult kidney transplant candidates with a positive crossmatch against an ABO-compatible deceased donor. These French consensus guidelines have been generated by an expert working group, in order to homogenize patient selection, associated treatments and follow-up. This initiative is part of an international effort to analyze properly the benefits and tolerance of this new costly treatment in real-life. Eligible patients must meet the following screening criteria: cPRA ≥ 98%, ≤ 65-year of age, ≥ 3 years on the waiting list, and a low risk of biopsy-related complications. The final decision to use Imlifidase will be based on the two following criteria. First, the results of a virtual crossmatch on recent serum, which shall show a MFI for the immunodominant donor-specific antibodies (DSA) > 6,000 but the value of which does not exceed 5,000 after 1:10 dilution. Second, the post-Imlifidase complement-dependent cytotoxicity crossmatch must be negative. Patients treated with Imlifidase will receive an immunosuppressive regimen based on steroids, rATG, high dose IVIg, rituximab, tacrolimus and mycophenolic acid. Frequent post-transplant testing for DSA and systematic surveillance kidney biopsies are highly recommended to monitor post-transplant DSA rebound and subclinical rejection.
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Affiliation(s)
- Lionel Couzi
- Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- CNRS-UMR 5164 Immuno ConcEpT, Université de Bordeaux, Bordeaux, France
| | - Paolo Malvezzi
- Centre Hospitalier Universitaire de Grenoble, La Tronche, France
| | | | | | - Gilles Blancho
- Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | | | - Marine Freist
- Centre Hospitalier Emile Roux, Le Puy-en-Velay, France
| | | | - Nassim Kamar
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | | | - Christophe Mariat
- Centre Hospitalier Universitaire (CHU) de Saint-Étienne, Saint-Etienne, France
| | | | - Johan Noble
- Centre Hospitalier Universitaire de Grenoble, La Tronche, France
| | | | - Antoine Thierry
- Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers, France
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14
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Mizera J, Pilch J, Giordano U, Krajewska M, Banasik M. Therapy in the Course of Kidney Graft Rejection-Implications for the Cardiovascular System-A Systematic Review. Life (Basel) 2023; 13:1458. [PMID: 37511833 PMCID: PMC10381422 DOI: 10.3390/life13071458] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/20/2023] [Accepted: 06/26/2023] [Indexed: 07/30/2023] Open
Abstract
Kidney graft failure is not a homogenous disease and the Banff classification distinguishes several types of graft rejection. The maintenance of a transplant and the treatment of its failure require specific medications and differ due to the underlying molecular mechanism. As a consequence, patients suffering from different rejection types will experience distinct side-effects upon therapy. The review is focused on comparing treatment regimens as well as presenting the latest insights into innovative therapeutic approaches in patients with an ongoing active ABMR, chronic active ABMR, chronic ABMR, acute TCMR, chronic active TCMR, borderline and mixed rejection. Furthermore, the profile of cardiovascular adverse effects in relation to the applied therapy was subjected to scrutiny. Lastly, a detailed assessment and comparison of different approaches were conducted in order to identify those that are the most and least detrimental for patients suffering from kidney graft failure.
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Affiliation(s)
- Jakub Mizera
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-551 Wroclaw, Poland
| | - Justyna Pilch
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-551 Wroclaw, Poland
| | - Ugo Giordano
- University Clinical Hospital, Wroclaw Medical University, 50-551 Wroclaw, Poland
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-551 Wroclaw, Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-551 Wroclaw, Poland
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15
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Tajima T, Hata K, Kusakabe J, Miyauchi H, Badshah JS, Kageyama S, Zhao X, Kim SK, Tsuruyama T, Kirchner VA, Watanabe T, Uemoto S, Hatano E. Anti-complement 5 antibody ameliorates antibody-mediated rejection after liver transplantation in rats. Front Immunol 2023; 14:1186653. [PMID: 37398677 PMCID: PMC10313232 DOI: 10.3389/fimmu.2023.1186653] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/18/2023] [Indexed: 07/04/2023] Open
Abstract
Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR.
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Affiliation(s)
- Tetsuya Tajima
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Jiro Kusakabe
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hidetaka Miyauchi
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Joshua Sam Badshah
- Department of Surgery , Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, United States
| | - Shoichi Kageyama
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Xiangdong Zhao
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Sung-Kwon Kim
- Alexion Pharmaceuticals Inc., New Haven, CT, United States
| | - Tatsuaki Tsuruyama
- Department of Drug Discovery Medicine, Pathology Division, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Varvara A. Kirchner
- Department of Surgery , Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, United States
| | - Takeshi Watanabe
- Division of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Shiga University of Medical Science, Otsu, Japan
| | - Etsuro Hatano
- Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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16
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Abstract
Access to kidney transplantation is limited by HLA-specific sensitization. Desensitization strategies enable crossmatch-positive kidney transplantation. In this review, we describe clinical experience gained over the last 20 y using desensitization strategies before kidney transplantation and describe the different tools used (both drugs and apheresis options), including IVIg, rituximab, apheresis techniques, interleukin-6 interference, proteasome inhibition, enzymatic degradation of HLA antibodies, complement inhibition, and B cytokine interference. Although access to transplantation for highly sensitized kidney transplantation candidates has been vastly improved by desensitization strategies, it remains, however, limited by the recurrence of HLA antibodies after transplantation and the occurrence of antibody-mediated rejection.
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17
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Sethi S, Jordan SC. Novel therapies for treatment of antibody-mediated rejection of the kidney. Curr Opin Organ Transplant 2023; 28:29-35. [PMID: 36579683 DOI: 10.1097/mot.0000000000001037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE OF REVIEW We aim to discuss current literature on novel therapies for antibody-mediated rejection (AMR) in kidney transplantation with a focus on chronic AMR. RECENT FINDINGS IL-6/IL-6 receptor blockers appear promising in the treatment of chronic AMR. Blocking this pathway was shown to reduce human leucocyte antigen-antibodies, improve histologic inflammation and increase T-regulatory cells. Based on experience in desensitization, IgG degrading endopeptidase, imlifidase, could be effective in AMR. There have been case reports describing the successful use of plasma cell/natural killer-cell-directed anti-CD38 antibody in the treatment of AMR. Off-target effects have been noted and strategies to mitigate these will be needed when using these agents. Complement inhibitors could be an effective add-on strategy to antibody-depleting therapies but their role in AMR needs to be better defined. Combining proteasome inhibitors and costimulation blockers has shown encouraging results in the prevention of AMR in animal models and is now being investigated in humans. Other novel strategies such as Fc neonatal receptor blockers which inhibit the recycling of pathogenic IgG and bispecific antibodies against B-cell maturation antigen/CD3+ T cells warrant further investigation. SUMMARY There are now a number of emerging therapies with varied targets and mechanism(s) of action that hold promise in the management of AMR and improving allograft survival.
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Affiliation(s)
- Supreet Sethi
- Division of Nephrology, Department of Medicine, Comprehensive Transplant Center, Cedars Sinai Medical Center, Los Angeles, California, USA
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18
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Vonbrunn E, Büttner-Herold M, Amann K, Daniel C. Complement Inhibition in Kidney Transplantation: Where Are We Now? BioDrugs 2023; 37:5-19. [PMID: 36512315 PMCID: PMC9836999 DOI: 10.1007/s40259-022-00567-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 12/14/2022]
Abstract
Kidney transplantation is a life-saving strategy for patients with end-stage renal disease. Although progress has been made in the field of transplantation medicine in recent decades in terms of surgical techniques and immunosuppression, long-term organ survival remains a challenge. Also, for reasons of organ shortage, there is an unmet need for new therapeutic approaches to improve the long-term survival of transplants. There is increasing evidence that the complement system plays a crucial role in various pathological events after transplantation, including ischemia/reperfusion injury as well as rejection episodes. The complement system is part of the innate immune system and plays a crucial role in the defense against pathogens but is also involved in tissue homeostasis. However, the tightly regulated complement system can become dysregulated or activated by non-infectious stimuli, then targeting the organism's own cells and leading to inflammatory tissue damage that exacerbates injury. In this review, we will highlight the role of the complement system after transplantation and discuss ongoing and potential therapeutic approaches.
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Affiliation(s)
- Eva Vonbrunn
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - Maike Büttner-Herold
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
| | - Christoph Daniel
- Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany
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19
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Novel Complement C5 Small-interfering RNA Lipid Nanoparticle Prolongs Graft Survival in a Hypersensitized Rat Kidney Transplant Model. Transplantation 2022; 106:2338-2347. [PMID: 35749284 DOI: 10.1097/tp.0000000000004207] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Prophylaxis of antibody-mediated rejection (AMR) caused by donor-specific antibodies remains challenging. Given the critical roles of complement activity in antibody-mediated graft injury, we developed a lipid nanoparticle (LNP) formulation of small-interfering RNA against complement C5 (C5 siRNA-LNP) and investigated whether C5 siRNA-LNP could downregulate the complement activity and act as an effective treatment for AMR. METHODS Lewis recipient rats were sensitized by skin grafting from Brown Norway donor rats. Kidney transplantation was performed at 4 wk post-skin grafting.C5 siRNA- or control siRNA-LNP was administered intravenously, and the weekly injections were continued until the study's conclusion. Cyclosporin (CsA) and/or deoxyspergualin (DSG) were used as adjunctive immunosuppressants. Complement activity was evaluated using hemolysis assays. The deposition of C5b9 in the grafts was evaluated using immunohistochemical analysis on day 7 posttransplantation. RESULTS C5 siRNA-LNP completely suppressed C5 expression and complement activity (hemolytic activity ≤ 20%) 7 d postadministration. C5 siRNA-LNP in combination with CsA and DSG (median survival time: 56.0 d) prolonged graft survival compared with control siRNA-LNP in combination with CsA and DSG (median survival time: 21.0 d; P = 0.0012; log-rank test). Immunohistochemical analysis of the grafts revealed that downregulation of C5 expression was associated with a reduction in C5b9-positive area ( P = 0.0141, Steel-Dwass test). CONCLUSIONS C5 siRNA-LNP combined with immunosuppressants CsA and DSG downregulated C5 activity and significantly prolonged graft survival compared with control siRNA-LNP with CsA and DSG. Downregulation of C5 expression using C5 siRNA-LNP may be an effective therapeutic approach for AMR.
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20
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Frutos MÁ, Crespo M, Valentín MDLO, Alonso-Melgar Á, Alonso J, Fernández C, García-Erauzkin G, González E, González-Rinne AM, Guirado L, Gutiérrez-Dalmau A, Huguet J, Moral JLLD, Musquera M, Paredes D, Redondo D, Revuelta I, Hofstadt CJVD, Alcaraz A, Alonso-Hernández Á, Alonso M, Bernabeu P, Bernal G, Breda A, Cabello M, Caro-Oleas JL, Cid J, Diekmann F, Espinosa L, Facundo C, García M, Gil-Vernet S, Lozano M, Mahillo B, Martínez MJ, Miranda B, Oppenheimer F, Palou E, Pérez-Saez MJ, Peri L, Rodríguez O, Santiago C, Tabernero G, Hernández D, Domínguez-Gil B, Pascual J. Recommendations for living donor kidney transplantation. Nefrologia 2022; 42 Suppl 2:5-132. [PMID: 36503720 DOI: 10.1016/j.nefroe.2022.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 06/17/2023] Open
Abstract
This Guide for Living Donor Kidney Transplantation (LDKT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes. Moreover, the role of living donors in the current KT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDKT, offer additional ways to treat renal patients with an incompatible donor. Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations. This Guide does not forget that LDKT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors' health. This aspect always has to be taken into account by LDKT programmes when evaluating potential donors. Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees.
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Affiliation(s)
| | - Marta Crespo
- Nephrology Department, Hospital del Mar, Barcelona, Spain
| | | | | | - Juana Alonso
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | | | - Esther González
- Nephrology Department, Hospital Universitario 12 Octubre, Spain
| | | | - Lluis Guirado
- Nephrology Department, Fundacio Puigvert, Barcelona, Spain
| | | | - Jorge Huguet
- RT Surgical Team, Fundació Puigvert, Barcelona, Spain
| | | | - Mireia Musquera
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | - David Paredes
- Donation and Transplantation Coordination Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Ignacio Revuelta
- Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Antonio Alcaraz
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | - Manuel Alonso
- Regional Transplantation Coordination, Seville, Spain
| | | | - Gabriel Bernal
- Nephrology Department, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Alberto Breda
- RT Surgical Team, Fundació Puigvert, Barcelona, Spain
| | - Mercedes Cabello
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | - Joan Cid
- Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Fritz Diekmann
- Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain
| | - Laura Espinosa
- Paediatric Nephrology Department, Hospital La Paz, Madrid, Spain
| | - Carme Facundo
- Nephrology Department, Fundacio Puigvert, Barcelona, Spain
| | | | | | - Miquel Lozano
- Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | | | | | | | - Eduard Palou
- Immunology Department, Hospital Clinic i Universitari, Barcelona, Spain
| | | | - Lluis Peri
- Urology Department, Hospital Clinic Universitari, Barcelona, Spain
| | | | | | | | - Domingo Hernández
- Nephrology Department, Hospital Regional Universitario de Málaga, Spain
| | | | - Julio Pascual
- Nephrology Department, Hospital del Mar, Barcelona, Spain.
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Yamamoto T, Pearson DS, Ababneh EI, Harris C, Nissaisorakarn P, Mahowald GK, Heher YK, Elias N, Markmann JF, Lewis GD, Riella LV. Case report: Successful simultaneous heart-kidney transplantation across a positive complement-dependent cytotoxic crossmatch. FRONTIERS IN NEPHROLOGY 2022; 2:1047217. [PMID: 37675007 PMCID: PMC10479575 DOI: 10.3389/fneph.2022.1047217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/11/2022] [Indexed: 09/08/2023]
Abstract
Preformed donor-specific antibodies are associated with a higher risk of rejection and worse graft survival in organ transplantation. However, in heart transplantation, the risk and benefit balance between high mortality on the waiting list and graft survival may allow the acceptance of higher immunologic risk donors in broadly sensitized recipients. Transplanting donor-recipient pairs with a positive complement dependent cytotoxic (CDC) crossmatch carries the highest risk of hyperacute rejection and immediate graft loss and is usually avoided in kidney transplantation. Herein we report the first successful simultaneous heart-kidney transplant with a T- and B-cell CDC crossmatch positive donor using a combination of rituximab, intravenous immunoglobulin, plasmapheresis, bortezomib and rabbit anti-thymocyte globulin induction followed by eculizumab therapy for two months post-transplant. In the year following transplantation, both allografts maintained stable graft function (all echocardiographic left ventricular ejection fractions ≥ 65%, eGFR>60) and showed no histologic evidence of antibody-mediated rejection. In addition, the patient has not developed any severe infections including cytomegalovirus or BK virus infection. In conclusion, a multitarget immunosuppressive regimen can allow for combined heart/kidney transplantation across positive CDC crossmatches without evidence of antibody-mediated rejection or significant infection. Longer follow-up will be needed to further support this conclusion.
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Affiliation(s)
- Takayuki Yamamoto
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
| | - Daniel S. Pearson
- Histocompatibility Laboratory, Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Emad I. Ababneh
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Cynthia Harris
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Pitchaphon Nissaisorakarn
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Division of Nephrology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
| | - Grace K. Mahowald
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Histocompatibility Laboratory, Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Yael K. Heher
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Department of Pathology, Massachusetts General Hospital, Boston, MA, United States
| | - Nahel Elias
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
| | - James F. Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
| | - Gregory D. Lewis
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
| | - Leonardo V. Riella
- Center for Transplantation Sciences, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
- Division of Nephrology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
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22
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Anwar IJ, DeLaura I, Ladowski J, Gao Q, Knechtle SJ, Kwun J. Complement-targeted therapies in kidney transplantation-insights from preclinical studies. Front Immunol 2022; 13:984090. [PMID: 36311730 PMCID: PMC9606228 DOI: 10.3389/fimmu.2022.984090] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/28/2022] [Indexed: 01/21/2023] Open
Abstract
Aberrant activation of the complement system contributes to solid-organ graft dysfunction and failure. In kidney transplantation, the complement system is implicated in the pathogenesis of antibody- and cell-mediated rejection, ischemia-reperfusion injury, and vascular injury. This has led to the evaluation of select complement inhibitors (e.g., C1 and C5 inhibitors) in clinical trials with mixed results. However, the complement system is highly complex: it is composed of more than 50 fluid-phase and surface-bound elements, including several complement-activated receptors-all potential therapeutic targets in kidney transplantation. Generation of targeted pharmaceuticals and use of gene editing tools have led to an improved understanding of the intricacies of the complement system in allo- and xeno-transplantation. This review summarizes our current knowledge of the role of the complement system as it relates to rejection in kidney transplantation, specifically reviewing evidence gained from pre-clinical models (rodent and nonhuman primate) that may potentially be translated to clinical trials.
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Affiliation(s)
| | | | | | | | - Stuart J. Knechtle
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC, United States
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Abstract
PURPOSE OF THE REVIEW Antibody-mediated rejection (AMR) is the leading cause of kidney graft loss. Very few treatment options are available to the clinician to counter this disease process. In this review we describe the available therapeutics and the novel approaches that are being currently developed. RECENT FINDINGS AMR treatment requires a multidrug approach. Imlifidase, a new immunoglobulin G cleaving agent, may prove to be the perfect replacement of apheresis. New complement blockers other than eculizumab are in development in order to block acute kidney damage in the delicate phase following antibody removal. Plasma cell depletion is being explored in chronic AMR: studies are in progress with daratumumab and felzartamab. Interleukin 6 inhibition is generating enthusiasm in the chronic setting with preliminary encouraging results. SUMMARY In acute AMR, the clinicians will have to remove the antibodies, avoid rebound and block specific damage effectors. In chronic AMR they will need to reduce the inflammatory response induced by donor specific antibodies. New drugs are available and transplant physicians are starting to develop effective multidrug strategies to counter the complex disease mechanisms. Safety of these drugs needs to be further explored especially when used together with other potent immunosuppressive drugs.
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Affiliation(s)
- Paolo Malvezzi
- University Grenoble Alpes - CHU Grenoble Alpes - Service de Néphrologie, Dialyse, Aphérèses et Transplantation, Grenoble, France
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24
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Cumpelik A, Heeger PS. Effects of the complement system on antibody formation and function: implications for transplantation. Curr Opin Organ Transplant 2022; 27:399-404. [PMID: 35857345 PMCID: PMC9474663 DOI: 10.1097/mot.0000000000001002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW In antibody-mediated allograft rejection, donor-reactive antibodies cause transplant injury in part via complement activation. New mechanistic insights indicate complement also modulates development of humoral immune responses. Herein we review recent data that describes how complement affects antibody formation and we discuss therapeutic implications. RECENT FINDINGS Extravasating T cells interacting with integrins express and activate intracellular complement that drives immune-metabolic adaptations vital for CD4 + helper cells. Marginal zone B cells can acquire intact major histocompatibility complexes from dendritic cells via complement-dependent trogocytosis for presentation to T cells. Activated B cells in germinal centers receive co-stimulatory signals from T-helper cells. These germinal center B cells undergo coordinate shifts in surface complement regulator expression that permit complement receptor signaling on the germinal center B cells required for affinity maturation. The positively selected, high-affinity B cells can differentiate into plasma cells that produce donor-HLA-reactive antibodies capable of ligating endothelial, among other, graft cells. Subsequent sublytic complement attack can stimulate endothelial cells to activate CD4 + and CD8 + T cells, promoting cellular and humoral rejection. Newly developed complement inhibitors are being tested to prevent/treat transplant rejection. SUMMARY The complement system influences T-cell, B-cell and endothelial-cell activation, and thereby contributes allograft injury. Emerging therapeutic strategies targeting complement activation have the potential to prevent or abrogate transplant injury and improve transplant outcomes.
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Affiliation(s)
- Arun Cumpelik
- Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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25
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Puissant-Lubrano B, Bouthemy C, Congy-Jolivet N, Milhes J, Minville V, Kamar N, Demini L, Zal F, Renaudineau Y. The oxygen carrier M101 alleviates complement activation, which may be beneficial for donor organ preservation. Front Immunol 2022; 13:1006761. [PMID: 36172347 PMCID: PMC9511029 DOI: 10.3389/fimmu.2022.1006761] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
During organ transplantation, ischemia/reperfusion injury and pre-formed anti-HLA antibodies are the main cause of delayed graft function and recovery through the activation of the complement system. By supplying oxygen during transplantation, M101 is suspected to avoid complement activation, however, a direct effect exerted by M101 on this pathway is unknown. This was tested by using functional assays (lymphocytotoxic crossmatch test, C3d Luminex-based assay, 50% complement hemolysis [CH50], and 50% alternative complement pathway [AP50/AH50]), and quantitative assays (C3, C3a, C4, C5, C5a, C6, C7, C8, C9 and sC5b-9). M101 interferes with the anti-HLA lymphocytotoxic crossmatch assay, and this effect is complement-dependent as M101 inhibits the classical complement pathway (CH50) in a dose-dependent and stable manner. Such inhibition was independent from a proteolytic effect (fractions C3 to C9) but related to a dose-dependent inhibition of the C3 convertase as demonstrated by exploring downstream the release of the anaphylatoxins (C3a and C5a), C3d, and sC5b-9. The C3 convertase inhibition in the presence of M101 was further demonstrated in the AP50/AH50 assay. In conclusion, the use of M101 avoids the activation of the complement pathway, which constitutes an additional advantage for this extracellular hemoglobin to preserve grafts from ischemia/reperfusion injury and preformed anti-HLA antibodies.
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Affiliation(s)
- Bénédicte Puissant-Lubrano
- Immunology department laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Center, Toulouse, France
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
| | - Charlène Bouthemy
- Immunology department laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Center, Toulouse, France
| | - Nicolas Congy-Jolivet
- Immunology department laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Center, Toulouse, France
- CRCT, INSERM UMR 1037, University Toulouse III, Toulouse, France
| | - Jean Milhes
- Immunology department laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Center, Toulouse, France
| | - Vincent Minville
- Department of Anesthesiology and Critical Care, Toulouse University Hospital Center, Toulouse, France
| | - Nassim Kamar
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
- Department of Nephrology and Organ Transplantation , Toulouse University Hospital Center, Toulouse, France
| | | | - Franck Zal
- HEMARINA, Aéropôle Centre, Morlaix, France
| | - Yves Renaudineau
- Immunology department laboratory, Institut Fédératif de Biologie, Toulouse University Hospital Center, Toulouse, France
- INFINITy, Toulouse Institute for Infectious and Inflammatory Diseases, INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France
- *Correspondence: Yves Renaudineau,
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26
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Kervella D, Le Bas-Bernardet S, Bruneau S, Blancho G. Protection of transplants against antibody-mediated injuries: from xenotransplantation to allogeneic transplantation, mechanisms and therapeutic insights. Front Immunol 2022; 13:932242. [PMID: 35990687 PMCID: PMC9389360 DOI: 10.3389/fimmu.2022.932242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/07/2022] [Indexed: 11/17/2022] Open
Abstract
Long-term allograft survival in allotransplantation, especially in kidney and heart transplantation, is mainly limited by the occurrence of antibody-mediated rejection due to anti-Human Leukocyte Antigen antibodies. These types of rejection are difficult to handle and chronic endothelial damages are often irreversible. In the settings of ABO-incompatible transplantation and xenotransplantation, the presence of antibodies targeting graft antigens is not always associated with rejection. This resistance to antibodies toxicity seems to associate changes in endothelial cells phenotype and modification of the immune response. We describe here these mechanisms with a special focus on endothelial cells resistance to antibodies. Endothelial protection against anti-HLA antibodies has been described in vitro and in animal models, but do not seem to be a common feature in immunized allograft recipients. Complement regulation and anti-apoptotic molecules expression appear to be common features in all these settings. Lastly, pharmacological interventions that may promote endothelial cell protection against donor specific antibodies will be described.
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Affiliation(s)
- Delphine Kervella
- CHU Nantes, Nantes Université, Néphrologie et Immunologie Clinique, Institut Transplantation Urologie Néphrologie (ITUN), Nantes, France
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Stéphanie Le Bas-Bernardet
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Sarah Bruneau
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Gilles Blancho
- CHU Nantes, Nantes Université, Néphrologie et Immunologie Clinique, Institut Transplantation Urologie Néphrologie (ITUN), Nantes, France
- Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
- *Correspondence: Gilles Blancho,
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27
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Antibodies against complement component C5 prevent antibody-mediated rejection after lung transplantation in murine orthotopic models with skin-graft-induced pre-sensitization. Gan To Kagaku Ryoho 2022; 70:1032-1041. [PMID: 35767165 DOI: 10.1007/s11748-022-01844-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 06/04/2022] [Indexed: 11/04/2022]
Abstract
OBJECTIVE Antibody-mediated rejection (AMR) could induce acute or chronic graft failure during organ transplantation. Several reports have shown that anti-C5 antibodies are effective against AMR after kidney transplantation. However, few reports have assessed the efficacy of anti-C5 antibodies against AMR after lung transplantation. Therefore, this study aimed to evaluate the efficacy of this novel therapy against AMR after lung transplantation. METHODS BALB/c and C57BL/6 mice were used as donors and recipients. One group was pre-sensitized (PS) by skin transplantation 14 days before lung transplantation. The other group was non-sensitized (NS). Orthotopic left-lung transplantation was performed in both groups. Animals were killed at 2 or 7 days after lung transplantation and evaluated for histopathology, C4d immunostaining, and serum donor-specific antibodies (DSAs) (n = 5 per group). Isograft (IS) models with C57BL/6 mice were used as controls. To evaluate the efficacy of C5 inhibition, other animals, which received similar treatments to those in the PS group, were treated with anti-C5 antibodies, cyclosporine/methylprednisolone, anti-C5 antibodies/cyclosporine/methylprednisolone, or isotype-matched irrelevant control monoclonal antibodies (n = 5 per group). RESULTS Two days after lung transplantation, the NS group exhibited mild, localized graft-rejection features (rejection score: 0.45 ± 0.08, p = 0.107). The PS group exhibited AMR features with a significantly higher rejection score (2.29 ± 0.42, p = 0.001), C4d vascular-endothelium deposition, and substantial presence of serum DSA. On day 7 after lung transplantation, both groups showed extensive graft alveolar wall destruction, and high acute-rejection scores. Mice receiving anti-C5 antibodies or anti-C5/antibodies/cyclosporine/methylprednisolone demonstrated significantly lower acute-rejection scores (0.63 ± 0.23, p = 0.002; 0.59 ± 0.22, p = 0.001, respectively) than those receiving isotype control antibodies. CONCLUSIONS Murine orthotopic allograft lung transplant models met the clinical diagnosis and pathogenesis classification criteria of AMR. In these models, anti-C5 antibodies suppressed AMR. Therefore, anti-C5 therapy may be effective against AMR after lung transplantation.
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28
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Szczepanik A, Choi D, Brady B, Chandran MM, Diamond A, Do V, Fredrick S, Kaiser T, Khalil K, Laub MR, Leino A, Park JM, Pierce D, Rendulic T, Wiegel JJ, Fose J, Jorgenson MR. The use of non-transplant biologics in solid organ transplant recipients: A practical review for the frontline clinician. Clin Transplant 2022; 36:e14743. [PMID: 35690919 DOI: 10.1111/ctr.14743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/09/2022] [Accepted: 06/01/2022] [Indexed: 11/27/2022]
Abstract
Biologics have become the forefront of medicine for management of autoimmune conditions, leading to improved quality of life. Many autoimmune conditions occur in solid organ transplant (SOT) recipients and persist following transplant. However, the use of biologics in this patient population is not well studied, and questions arise related to risk of infection and adjustments to induction and maintenance immunosuppression. Guidelines have been published highlighting management strategies of biologics around the time of elective surgical procedures, but this is not always feasible in urgent situations, especially with deceased donor transplantation. The aim of this review is to summarize the current literature regarding the use of these agents in solid organ transplant recipients, and specifically address induction and maintenance immunosuppression, as well as the need for alternative infective prevention strategies to create a practical reference for the frontline clinician, when faced with this complex clinical scenario.
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Affiliation(s)
- Amanda Szczepanik
- Department of Pharmacy, University of Maryland Medical Center, Baltimore, Maryland, USA
| | - David Choi
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, USA
| | | | | | | | - Vincent Do
- Department of Pharmacy, Yale New Haven Hospital, New Haven, Connecticut, USA
| | | | | | | | - Melissa R Laub
- Department of Pharmacy, Augusta University Medical Center, Augusta, Georgia, USA
| | - Abbie Leino
- Department of Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeong M Park
- Department of Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Dana Pierce
- Department of Pharmacy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
| | | | | | - Jillian Fose
- Department of Pharmacy, UW Health, Madison, Wisconsin, USA
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29
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Recomendaciones para el trasplante renal de donante vivo. Nefrologia 2022. [DOI: 10.1016/j.nefro.2021.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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30
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Kher V, Kute VB, Sahariah S, Ray DS, Khullar D, Guleria S, Bansal S, Gang S, Bhalla AK, Prakash J, Abraham A, Shroff S, Bahadur MM, Das P, Anandh U, Chaudhury AR, Singhal M, Kothari J, Raju SB, Pahari DK, Siddini GV, Sudhakar G, Varughese S, Saha TK. Clinical Perspectives towards Improving Risk Stratification Strategy for Renal Transplantation Outcomes in Indian Patients. INDIAN JOURNAL OF TRANSPLANTATION 2022; 16:145-154. [DOI: 10.4103/ijot.ijot_28_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Graft loss and rejections (acute/chronic) continue to remain important concerns in long-term outcomes in kidney transplant despite newer immunosuppressive regimens and increased use of induction agents. Global guidelines identify the risk factors and suggest a framework for management of patients at different risk levels for rejection; however, these are better applicable to deceased donor transplants. Their applicability in Indian scenario (predominantly live donor program) could be a matter of debate. Therefore, a panel of experts discussed the current clinical practice and adaptability of global recommendations to Indian settings. They also took a survey to define risk factors in kidney transplants and provide direction toward evidence- and clinical experience-based risk stratification for donor/recipient and transplant-related characteristics, with a focus on living donor transplantations. Several recipient related factors (dialysis, comorbidities, and age, donor-specific antibodies [DSAs]), donor-related factors (age, body mass index, type – living or deceased) and transplantation related factors (cold ischemia time [CIT], number of transplantations) were assessed. The experts suggested that immunological conflict should be avoided by performing cytotoxic cross match, flow cross match in all patients and DSA-(single antigen bead) whenever considered clinically relevant. HLA mismatches, presence of DSA, along with donor/recipient age, CIT, etc., were associated with increased risk of rejection. Furthermore, the panel agreed that the risk of rejection in living donor transplant is not dissimilar to deceased donor recipients. The experts also suggested that induction immunosuppression could be individualized based on the risk stratification.
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31
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Salvadori M, Tsalouchos A. Innovative immunosuppression in kidney transplantation: A challenge for unmet needs. World J Transplant 2022; 12:27-41. [PMID: 35433332 PMCID: PMC8968476 DOI: 10.5500/wjt.v12.i3.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 01/27/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.
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Affiliation(s)
- Maurizio Salvadori
- Department of Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Division of Nephrology, Santa Maria Annunziata Hospital, Florence 50012, Italy
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32
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Kamel MH, Jaberi A, Gordon CE, Beck LH, Francis J. The Complement System in the Modern Era of Kidney Transplantation: Mechanisms of Injury and Targeted Therapies. Semin Nephrol 2022; 42:14-28. [DOI: 10.1016/j.semnephrol.2022.01.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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33
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Nikolova A, Patel JK. Induction Therapy and Therapeutic Antibodies. Handb Exp Pharmacol 2022; 272:85-116. [PMID: 35474024 DOI: 10.1007/164_2021_570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Prevention of allograft rejection is one of the crucial goals in solid organ transplantation to ensure durability of the graft and is chiefly mediated by cellular and humoral pathways targeting cell surface alloantigens. The risk of rejection is highest in the first post-transplant year and wanes with time albeit the risk always exists and varies with the type of organ transplanted. Induction therapies refer to the use of high-intensity immunosuppression in the immediate post-operative period to mitigate the highest risk of rejection. This term encompasses chiefly the use of antibody therapies directed against one of the key pathways in T-cell activation or abrogating effects of circulating alloantibodies. These antibodies carry more potent immunomodulatory effect than maintenance immunosuppressive therapy alone and many of them lead to durable immune cell depletion. A variety of monoclonal and polyclonal antibodies have been utilized for use not only for induction therapy, but also for treatment of allograft rejection when it occurs and as components of desensitization therapy before and after transplantation to modulate circulating alloantibodies.
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Witczak BJ, Pischke SE, Reisæter AV, Midtvedt K, Ludviksen JK, Heldal K, Jenssen T, Hartmann A, Åsberg A, Mollnes TE. Elevated Terminal C5b-9 Complement Complex 10 Weeks Post Kidney Transplantation Was Associated With Reduced Long-Term Patient and Kidney Graft Survival. Front Immunol 2021; 12:738927. [PMID: 34759922 PMCID: PMC8573334 DOI: 10.3389/fimmu.2021.738927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 10/04/2021] [Indexed: 11/25/2022] Open
Abstract
Background The major reason for graft loss is chronic tissue damage, as interstitial fibrosis and tubular atrophy (IF/TA), where complement activation may serve as a mediator. The association of complement activation in a stable phase early after kidney transplantation with long-term outcomes is unexplored. Methods We examined plasma terminal C5b-9 complement complex (TCC) 10 weeks posttransplant in 900 patients receiving a kidney between 2007 and 2012. Clinical outcomes were assessed after a median observation time of 9.3 years [interquartile range (IQR) 7.5–10.6]. Results Elevated TCC plasma values (≥0.7 CAU/ml) were present in 138 patients (15.3%) and associated with a lower 10-year patient survival rate (65.7% vs. 75.5%, P < 0.003). Similarly, 10-year graft survival was lower with elevated TCC; 56.9% vs. 67.3% (P < 0.002). Graft survival was also lower when censored for death; 81.5% vs. 87.3% (P = 0.04). In multivariable Cox analyses, impaired patient survival was significantly associated with elevated TCC [hazard ratio (HR) 1.40 (1.02–1.91), P = 0.04] along with male sex, recipient and donor age, smoking, diabetes, and overall survival more than 1 year in renal replacement therapy prior to engraftment. Likewise, elevated TCC was independently associated with graft loss [HR 1.40 (1.06–1.85), P = 0.02] along with the same covariates. Finally, elevated TCC was in addition independently associated with death-censored graft loss [HR 1.69 (1.06–2.71), P = 0.03] as were also HLA-DR mismatches and higher immunological risk. Conclusions Early complement activation, assessed by plasma TCC, was associated with impaired long-term patient and graft survival.
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Affiliation(s)
| | - Søren E Pischke
- Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway.,Department of Anaesthesiology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Anna V Reisæter
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway.,Norwegian Renal Registry, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Karsten Midtvedt
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | | | - Kristian Heldal
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway
| | - Trond Jenssen
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Anders Hartmann
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Anders Åsberg
- Department of Transplantation Medicine, Oslo University Hospital-Rikshospitalet, Oslo, Norway.,Norwegian Renal Registry, Oslo University Hospital-Rikshospitalet, Oslo, Norway.,Department of Pharmacy, University of Oslo, Oslo, Norway
| | - Tom E Mollnes
- Department of Immunology, Oslo University Hospital, University of Oslo, Oslo, Norway.,Research Laboratory, Nordland Hospital, Bodø, Norway.,Faculty of Health Sciences, KG Jebsen Thrombosis Research and Expertise Center (TREC), University of Tromsø, Tromsø, Norway.,Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway
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35
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Howard MC, Nauser CL, Farrar CA, Sacks SH. Complement in ischaemia-reperfusion injury and transplantation. Semin Immunopathol 2021; 43:789-797. [PMID: 34757496 PMCID: PMC8579729 DOI: 10.1007/s00281-021-00896-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/22/2021] [Indexed: 01/08/2023]
Abstract
Until recently, the only known condition in which complement could mediate transplant injury was the rare occurrence of antibody-mediated rejection, in which the original concept of antibody immunity against the transplant was supported by complementary proteins present in the serum. This has changed within the last two decades because of evidence that the processes of ischaemia–reperfusion injury followed by T cell–mediated rejection are also critically dependent on components generated by the complement system. We now have a clearer understanding of the complement triggers and effectors that mediate injury, and a detailed map of their local sites of production and activation in the kidney. This is providing helpful guidelines as to how these harmful processes that restrict transplant outcomes can be targeted for therapeutic benefit. Here we review some of the recent advances highlighting relevant therapeutic targets.
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Affiliation(s)
- Mark C Howard
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.
| | - Christopher L Nauser
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Conrad A Farrar
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
| | - Steven H Sacks
- Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, 5thFloor Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK
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Sethi S, Ammerman N, Vo A, Jordan SC. Approach to Highly Sensitized Kidney Transplant Candidates and a Positive Crossmatch. Adv Chronic Kidney Dis 2021; 28:587-595. [PMID: 35367027 DOI: 10.1053/j.ackd.2021.09.004] [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: 05/29/2021] [Accepted: 09/08/2021] [Indexed: 11/11/2022]
Abstract
Human leukocyte antigen (HLA)-incompatible kidney transplantation offers survival benefit compared with ongoing dialysis. There have been considerable advances in the last decade to allow for increased access to transplant for the HLA-sensitized kidney transplant candidates. These include increased priority in the kidney allocation system, kidney paired donation, and novel desensitization strategies. A better understanding of the role of B cells, plasma cells, and complement and inflammatory cytokines in the pathophysiology of HLA antibody-mediated allograft injury has led to the use of novel therapeutics for desensitization and treatment of antibody-mediated rejection. Here we discuss current approaches to kidney transplantation in HLA-sensitized kidney transplant candidates.
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37
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Storti G, Favi E, Albanesi F, Kim BS, Cervelli V. Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives. Int J Mol Sci 2021; 22:11188. [PMID: 34681848 PMCID: PMC8538841 DOI: 10.3390/ijms222011188] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia-reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.
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Affiliation(s)
- Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, Italy; (G.S.); (V.C.)
| | - Evaldo Favi
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy;
| | - Francesca Albanesi
- Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy;
| | - Bong-Sung Kim
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, Italy; (G.S.); (V.C.)
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38
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Abstract
Complement is an evolutionarily conserved system which is important in the defense against microorganisms and also in the elimination of modified or necrotic elements of the body. Complement is activated in a cascade type manner and activation and all steps of cascade progression are tightly controlled and regulatory interleaved with many processes of inflammatory machinery. Overshooting of the complement system due to dysregulation can result in the two prototypes of primary complement mediated renal diseases: C3 glomerulopathy and thrombotic microangiopathy. Apart from these, complement also is highly activated in many other inflammatory native kidney diseases, such as membranous nephropathy, ANCA-associated necrotizing glomerulonephritis, and IgA nephropathy. Moreover, it likely plays an important role also in the transplant setting, such as in antibody-mediated rejection or in hematopoietic stem cell transplant associated thrombotic microangiopathy. In this review, these glomerular disorders are discussed with regard to the role of complement in their pathogenesis. The consequential, respective clinical trials for complement inhibitory therapy strategies for these diseases are described.
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Abstract
PURPOSE OF REVIEW In this review, we discuss achievements in immunosuppression in kidney transplant recipients published at last 18 months. RECENT FINDINGS Results of recent trials with everolimus in low-risk primary kidney transplant recipients suggest that lowTAC/EVR combination is noninferior and CMV and BKV viral infections are less frequent to standTAC/MPA. Iscalimab monoclonal antibody, which prevents CD40 to CD154 binding, has just recently entered phase II clinical studies in kidney transplantation. Eculizumab, anti-C5 monoclonal antobody was recently shown to improve outcomes in DSA+ living-donor kidney transplant recipients requiring pretransplant desensitization because of crossmatch positivity. Proximal complement C1 inhibition in patients with antibody-mediated rejection was studied in several phase I trials. SUMMARY Recent knowledge creates a path towards future immunosuppression success in sensitized recipients and in those in high risk of viral infections or CNI nephrotoxicity.
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40
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Fukui S, Hidaka M, Fukui S, Morimoto S, Hara T, Soyama A, Adachi T, Matsushima H, Tanaka T, Fuchigami M, Hasegawa H, Yanagihara K, Eguchi S. The Contribution of Serum Complement Component 3 Levels to 90-Day Mortality in Living Donor Liver Transplantation. Front Immunol 2021; 12:652677. [PMID: 34349754 PMCID: PMC8326795 DOI: 10.3389/fimmu.2021.652677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 06/28/2021] [Indexed: 11/13/2022] Open
Abstract
The contributions of the complement system have been elucidated in the process of solid organ transplantation, including kidney transplantation. However, the role of complement in liver transplantation is unknown. We sought to elucidate the time-dependent changes of peritransplantational serum complement levels and the relationships with posttransplant outcomes and other immunological biomarkers. We enrolled 82 patients who underwent living-related donor liver transplantation (LDLT). Nine patients (11%) died within 90 days after LDLT (non-survivors). The following immunomarkers were collected preoperatively and at 1, 2, and 4 week(s) after LDLT: serum C3, C4, immunoglobulin G (IgG), and peripheral blood leukocyte populations characterized by CD3, CD4, CD8, CD16, CD19, CD20, CD22, and CD56. Consequently, C3 and C4 increased time-dependently after LDLT. Preoperatively, C3 was negatively correlated with the MELD score, Child–Pugh score, CD16-positive leukocyte percentage, and the CD56-positive leukocyte percentage. Non-survivors had lower levels of C3 at 2 weeks in comparison to survivors (median [interquartile range]: 56 [49-70] mg/dL vs. 88 [71-116] mg/dL, p=0.0059). When the cutoff value of C3 at 2 weeks to distinguish non-survivors was set to 71 mg/dL, the sensitivity, specificity, and area under the ROC curve were 87.5%, 75.0%, and 0.80, respectively. A principal component analysis showed an inverse relationship between the C3 and C4 levels and the percentage of CD8-, CD16-, and CD56-positive leukocytes at 1 and 2 week(s). All non-survivors were included in the cluster that showed higher percentages of CD8-, CD16-, and CD56-positive leukocytes at 2 weeks. In conclusion, we demonstrated the relationship between complement, outcomes, and other immunomarkers in LDLT and suggested the usefulness of C3 at 2 weeks after LDLT in distinguishing the mortality.
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Affiliation(s)
- Saeko Fukui
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Shoichi Fukui
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, United States
| | - Shimpei Morimoto
- Innovation Platform & Office for Precision Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Hajime Matsushima
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Takayuki Tanaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
| | - Mai Fuchigami
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Hiroo Hasegawa
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Katsunori Yanagihara
- Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Science, Nagasaki, Japan
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41
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Novel Insights into the Molecular Mechanisms of Ischemia/Reperfusion Injury in Kidney Transplantation. TRANSPLANTOLOGY 2021. [DOI: 10.3390/transplantology2020018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ischemia reperfusion injury (IRI) is one of the most important mechanisms involved in delayed or reduced graft function after kidney transplantation. It is a complex pathophysiological process, followed by a pro-inflammatory response that enhances the immunogenicity of the graft and the risk of acute rejection. Many biologic processes are involved in its development, such as transcriptional reprogramming, the activation of apoptosis and cell death, endothelial dysfunction and the activation of the innate and adaptive immune response. Recent evidence has highlighted the importance of complement activation in IRI cascade, which expresses a pleiotropic action on tubular cells, on vascular cells (pericytes and endothelial cells) and on immune system cells. The effects of IRI in the long term lead to interstitial fibrosis and tubular atrophy, which contribute to chronic graft dysfunction and subsequently graft failure. Furthermore, several metabolic alterations occur upon IRI. Metabolomic analyses of IRI detected a “metabolic profile” of this process, in order to identify novel biomarkers that may potentially be useful for both early diagnosis and monitoring the therapeutic response. The aim of this review is to update the most relevant molecular mechanisms underlying IRI, and also to discuss potential therapeutic targets in future clinical practice.
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Schinstock C, Tambur A, Stegall M. Current Approaches to Desensitization in Solid Organ Transplantation. Front Immunol 2021; 12:686271. [PMID: 34046044 PMCID: PMC8144637 DOI: 10.3389/fimmu.2021.686271] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 04/26/2021] [Indexed: 11/13/2022] Open
Abstract
Major advancements in the development of HLA antibody detection techniques and our understanding of the outcomes of solid organ transplant in the context of HLA antibody have occurred since the relevance of sensitization was first recognized nearly 50 years ago. Additionally, kidney paired donation programs (KPD) have become widespread, deceased donor allocation policies have changed, and several new therapeutic options have become available with promise to reduce HLA antibody. In this overview we aim to provide thoughtful guidance about when desensitization in kidney transplantation should be considered taking into account the outcomes of HLA incompatible transplantation. Novel therapeutics, desensitization endpoints, and strategies for future study will also be discussed. While most of our understanding about desensitization comes from studying kidney transplant candidates and recipients, many of the concepts discussed can be easily applied to desensitization in all of solid organ transplantation.
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Affiliation(s)
- Carrie Schinstock
- William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, United States
| | - Anat Tambur
- Department of Surgery, Northwestern University, Chicago, IL, United States
| | - Mark Stegall
- William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, United States
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43
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Kim MY, Brennan DC. Therapies for Chronic Allograft Rejection. Front Pharmacol 2021; 12:651222. [PMID: 33935762 PMCID: PMC8082459 DOI: 10.3389/fphar.2021.651222] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/10/2021] [Indexed: 12/14/2022] Open
Abstract
Remarkable advances have been made in the pathophysiology, diagnosis, and treatment of antibody-mediated rejection (ABMR) over the past decades, leading to improved graft outcomes. However, long-term failure is still high and effective treatment for chronic ABMR, an important cause of graft failure, has not yet been identified. Chronic ABMR has a relatively different phenotype from active ABMR and is a slowly progressive disease in which graft injury is mainly caused by de novo donor specific antibodies (DSA). Since most trials of current immunosuppressive therapies for rejection have focused on active ABMR, treatment strategies based on those data might be less effective in chronic ABMR. A better understanding of chronic ABMR may serve as a bridge in establishing treatment strategies to improve graft outcomes. In this in-depth review, we focus on the pathophysiology and characteristics of chronic ABMR along with the newly revised Banff criteria in 2017. In addition, in terms of chronic ABMR, we identify the reasons for the resistance of current immunosuppressive therapies and look at ongoing research that could play a role in setting better treatment strategies in the future. Finally, we review non-invasive biomarkers as tools to monitor for rejection.
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Affiliation(s)
| | - Daniel C. Brennan
- Department of Internal Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
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Infectious Risks Associated with Biologics Targeting Janus Kinase-Signal Transducer and Activator of Transcription Signaling and Complement Pathway for Inflammatory Diseases. Infect Dis Clin North Am 2021; 34:271-310. [PMID: 32444011 DOI: 10.1016/j.idc.2020.02.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The recognition of the role of complement and Janus kinase (JAK)-dependent cytokines in the pathogenesis of inflammatory and immune-mediated disorders has revolutionized the treatment of a myriad of rheumatological and inflammatory diseases. C5 inhibitors and Janus kinase inhibitors have emerged as attractive therapeutic options. Because of the blockage of immune pathways, these targeted therapies carry an increased risk of infection. This article reviews the mechanism of action and the approved and off-label indications of the agents with most clinical experience within this drug classes. It discusses the associated risks of infection, proposing screening, prevention, and risk mitigation strategies.
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45
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Pilch NA, Bowman LJ, Taber DJ. Immunosuppression trends in solid organ transplantation: The future of individualization, monitoring, and management. Pharmacotherapy 2020; 41:119-131. [PMID: 33131123 DOI: 10.1002/phar.2481] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/07/2020] [Accepted: 08/09/2020] [Indexed: 12/20/2022]
Abstract
Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70 years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1-year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immunoreactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under- and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long-term outcomes during the next era of immunosuppression, which will move from universal protocols to patient-specific optimization.
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Affiliation(s)
- Nicole A Pilch
- Department of Pharmacy Practice and Outcomes Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lyndsey J Bowman
- Department of Pharmacy, Tampa General Hospital, Tampa, Florida, USA
| | - David J Taber
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.,Department of Pharmacy Services, Ralph H. Johnson VAMC, Charleston, South Carolina, USA
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46
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Cheng C, Cheng GY, Denas G, Pengo V. Arterial thrombosis in antiphospholipid syndrome (APS): Clinical approach and treatment. A systematic review. Blood Rev 2020; 48:100788. [PMID: 33341301 DOI: 10.1016/j.blre.2020.100788] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 11/17/2020] [Accepted: 12/08/2020] [Indexed: 12/17/2022]
Abstract
Thrombotic Antiphospholipid Syndrome (APS) is a condition affecting young individuals in whom a thromboembolic event occurs in the presence of circulating antiphospholipid antibodies (aPL). An extensive body of literature has covered the most common clinical presentation of the syndrome, venous thromboembolism. Arterial thrombosis in APS, a lesser clinical expression, is less studied. This review will concentrate on the body of literature concerning pathogenesis, clinical presentation and management of arterial thrombosis in APS.
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Affiliation(s)
- Chunyan Cheng
- Thrombosis Research Laboratory, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padua, Italy
| | - Gang-Yi Cheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Gentian Denas
- Thrombosis Research Laboratory, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padua, Italy
| | - Vittorio Pengo
- Thrombosis Research Laboratory, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padova, Padua, Italy; Arianna Foundation on Anticoagulation, Bologna, Italy.
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47
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Ort M, Dingemanse J, van den Anker J, Kaufmann P. Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Front Immunol 2020; 11:599417. [PMID: 33362783 PMCID: PMC7758461 DOI: 10.3389/fimmu.2020.599417] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 11/09/2020] [Indexed: 12/15/2022] Open
Abstract
The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented.
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Affiliation(s)
- Marion Ort
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.,Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland
| | - Jasper Dingemanse
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
| | - John van den Anker
- Pediatric Pharmacology and Pharmacometrics, University Children's Hospital Basel (UKBB), University of Basel, Basel, Switzerland.,Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, United States
| | - Priska Kaufmann
- Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
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Suchanek O, Clatworthy MR. Novel strategies to target the humoral alloimmune response. HLA 2020; 96:667-680. [PMID: 33022883 DOI: 10.1111/tan.14092] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 10/02/2020] [Accepted: 10/03/2020] [Indexed: 12/24/2022]
Abstract
Antibody-mediated rejection (ABMR) represents a major cause of late allograft loss in solid organ transplantation worldwide. This process is driven by donor-specific antibodies (DSA), which develop either de-novo or, in sensitized patients, are preformed at the time of transplantation. Effective targeting of ABMR has been hampered by a lack of robust randomized controlled trials (RCT), required for the regulatory approval of new therapeutics. In this review, we discuss the evidence behind the present "standard" of care and recent progress in the development of novel strategies targeting different aspects of the alloimmune humoral response, including naïve and memory B-cell activation, the germinal centre reaction, plasma cell survival and antibody effector functions. In particular, we focus on co-stimulation blockade and its combination with next-generation proteasome inhibitors, new depleting monoclonal antibodies (anti-CD19, anti-BCMA, anti-CD38, anti-CD138), interleukin-6 blockade, complement inhibition and DSA degradation. These treatment modalities, when used in the appropriate clinical context and combination, have the potential to finally improve long-term allograft survival.
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Affiliation(s)
- Ondrej Suchanek
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Menna R Clatworthy
- Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
- Cambridge University Hospitals NHS Foundation Trust, NIHR Cambridge Biomedical Research Centre, Cambridge, UK
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
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Abstract
PURPOSE OF REVIEW This review summarises recent developments in monitoring and immunosuppressive management in kidney transplantation. RECENT FINDINGS Long-term kidney allograft outcomes have not changed substantially mainly as a result of acute and chronic antibody-mediated rejection. Several groups have recently attempted to determine peripheral molecular fingerprints of ongoing rejection. But while this research is promising, it is not generalised for further spreading among different cohorts. Measurements of donor-derived cell-free DNA levels in recent studies have revealed better predictive values for antibody-mediated rejection. The Molecular Microscope Diagnostic System for assessing kidney graft biopsies has been gradually introduced within clinical practice, especially in complicated cases aimed at improving histological diagnostics. Molecular studies on accommodation in ABO-incompatible transplantation have shown increased complement regulation and lower expression of epithelial transporters and class 1 metallothioneins. Additionally, in clinical studies of sensitised patients, imlifidase has been shown to enable transplantation across significant immunological barriers, while the co-stimulation blockade has been tested to prevent donor specific antibodies development. In low-risk patients, everolimus/tacrolimus-based regimens have also proven their antiviral effects in large clinical trials. SUMMARY Recent developments in non-invasive monitoring have paved the way for the introduction of future larger clinical trials with multiple patient cohorts.
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Nanno Y, Burlak C. Xenotransplantation literature update, July/August 2020. Xenotransplantation 2020; 27:e12653. [PMID: 33020943 DOI: 10.1111/xen.12653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 11/29/2022]
Affiliation(s)
- Yoshihide Nanno
- Department of Surgery, Schultz Diabetes Institute, University of Minnesota, Minneapolis, MN, USA
| | - Christopher Burlak
- Department of Surgery, Schultz Diabetes Institute, University of Minnesota, Minneapolis, MN, USA
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