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1
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van Zyl M, Cramer E, Sanders JSF, Leuvenink HGD, Lisman T, van Rooy MJ, Hillebrands JL. The role of neutrophil extracellular trap formation in kidney transplantation: Implications from donors to the recipient. Am J Transplant 2024; 24:1547-1557. [PMID: 38719094 DOI: 10.1016/j.ajt.2024.04.018] [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: 01/19/2024] [Revised: 03/19/2024] [Accepted: 04/05/2024] [Indexed: 05/23/2024]
Abstract
Kidney transplantation remains the gold standard for patients with end-stage renal disease, but severe donor organ shortage has led to long waiting lists. The utilization of expanded criteria donor kidneys within the category of deceased donors has enlarged the pool of available kidneys for transplantation; however, these grafts often have an increased risk for delayed graft function or reduced graft survival following transplantation. During brain or circulatory death, neutrophils are recruited to the vascular beds of kidneys where a proinflammatory microenvironment might prime the formation of neutrophil extracellular traps (NETs), web-like structures, containing proteolytic enzymes, DNA, and histones. NETs are known to cause tissue damage and specifically endothelial damage while activating other systems such as coagulation and complement, contributing to tissue injury and an unfavorable prognosis in various diseases. In lung transplantation and kidney transplantation studies, NETs have also been associated with primary graft dysfunction or rejection. In this review, the role that NETs might play across the different phases of transplantation, already initiated in the donor, during preservation, and in the recipient, will be discussed. Based on current knowledge, NETs might be a promising therapeutic target to improve graft outcomes.
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Affiliation(s)
- Maryna van Zyl
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands; Department of Physiology, School of Medicine, University of Pretoria, Pretoria, South Africa
| | - Elodie Cramer
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | - Jan-Stephan F Sanders
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, the Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Ton Lisman
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - Mia-Jeanne van Rooy
- Department of Physiology, School of Medicine, University of Pretoria, Pretoria, South Africa
| | - Jan-Luuk Hillebrands
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands.
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2
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Stea ED, D'Ettorre G, Mitrotti A, Gesualdo L. The complement system in the pathogenesis and progression of kidney diseases: What doesn't kill you makes you older. Eur J Intern Med 2024; 124:22-31. [PMID: 38461065 DOI: 10.1016/j.ejim.2024.02.015] [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: 09/16/2023] [Revised: 01/31/2024] [Accepted: 02/09/2024] [Indexed: 03/11/2024]
Abstract
The Complement System is an evolutionarily conserved component of immunity that plays a key role in host defense against infections and tissue homeostasis. However, the dysfunction of the Complement System can result in tissue damage and inflammation, thereby contributing to the development and progression of various renal diseases, ranging from atypical Hemolytic Uremic Syndrome to glomerulonephritis. Therapeutic interventions targeting the complement system have demonstrated promising results in both preclinical and clinical studies. Currently, several complement inhibitors are being developed for the treatment of complement-mediated renal diseases. This review aims to summarize the most recent insights into complement activation and therapeutic inhibition in renal diseases. Furthermore, it offers potential directions for the future rational use of complement inhibitor drugs in the context of renal diseases.
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Affiliation(s)
- Emma Diletta Stea
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy
| | | | - Adele Mitrotti
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), Nephrology and Urology Units, University of Bari Aldo Moro, Bari, Italy.
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3
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Bhattarai D, Lee SO, Joshi N, Jun SR, Lo S, Jiang L, Gokden N, Parajuli N. Cold Storage Followed by Transplantation Induces Immunoproteasome in Rat Kidney Allografts: Inhibition of Immunoproteasome Does Not Improve Function. KIDNEY360 2024; 5:743-752. [PMID: 38303110 PMCID: PMC11146655 DOI: 10.34067/kid.0000000000000368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 01/12/2024] [Indexed: 02/03/2024]
Abstract
Key Points Cold storage (CS) increases the severity of graft dysfunction in a time-dependent manner, and prolonged CS decreases animal survival. CS plus transplant increases iproeasome levels/assembly in renal allografts; IFN-γ is a potential inducer of the iproteasome. Inhibiting iproteasome ex vivo during renal CS did not confer graft protection after transplantation. Background It is a major clinical challenge to ensure the long-term function of transplanted kidneys. Specifically, the injury associated with cold storage (CS) of kidneys compromises the long-term function of the grafts after transplantation. Therefore, the molecular mechanisms underlying CS-related kidney injury are attractive therapeutic targets to prevent injury and improve long-term graft function. Previously, we found that constitutive proteasome function was compromised in rat kidneys after CS followed by transplantation. Here, we evaluated the role of the immunoproteasome (i proteasome), a proteasome variant, during CS followed by transplantation. Methods Established in vivo rat kidney transplant model with or without CS containing vehicle or iproteasome inhibitor (ONX 0914) was used in this study. The i proteasome function was performed using rat kidney homogenates and fluorescent-based peptide substrate specific to β 5i subunit. Western blotting and quantitative RT-PCR were used to assess the subunit expression/level of the i proteasome (β 5i) subunit. Results We demonstrated a decrease in the abundance of the β 5i subunit of the i proteasome in kidneys during CS, but β 5i levels increased in kidneys after CS and transplant. Despite the increase in β 5i levels and its peptidase activity within kidneys, inhibiting β 5i during CS did not improve graft function after transplantation. Summary These results suggest that the pharmacologic inhibition of immunoproteasome function during CS does not improve graft function or outcome. In light of these findings, future studies targeting immunoproteasomes during both CS and transplantation may define the role of immunoproteasomes on short-term and long-term kidney transplant outcomes.
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Affiliation(s)
- Dinesh Bhattarai
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Seong-Ok Lee
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Neelam Joshi
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Se-Ran Jun
- Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Sorena Lo
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Li Jiang
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Neriman Gokden
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Nirmala Parajuli
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
- Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
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4
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Sana Vilela V, Andrighetti de Oliveira Braga K, Moreira Ruiz L, Nepomuceno NA, Oliveira Melo P, Manzuti GM, Alcantara de Oliveira Costa V, de Campos Ramos J, Tadeu Correia A, Pêgo-Fernandes PM. Anti-inflammatory effect of thalidomide in an experimental lung donor model of brain death. Sci Rep 2024; 14:8796. [PMID: 38627574 PMCID: PMC11021429 DOI: 10.1038/s41598-024-59267-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 04/09/2024] [Indexed: 04/19/2024] Open
Abstract
Lung transplantation stands as a vital treatment for severe lung diseases, primarily sourcing organs from donors with brain death (BD). This research delved into the potential anti-inflammatory effects of thalidomide in rats with BD-induced lung complications. In this study twenty-four Wistar rats were divided into three groups: the control (CTR), brain death (BD) and brain death + thalidomide (TLD) groups. Post specific procedures, a 360 min monitoring period ensued. Comprehensive analyses of blood and heart-lung samples were conducted. Elevated IL-6 levels characterized both BD and TLD groups relative to the CTR (p = 0.0067 and p = 0.0137). Furthermore, TNF-α levels were notably higher in the BD group than both CTR and TLD (p = 0.0152 and p = 0.0495). Additionally, IL-1β concentrations were significantly pronounced in both BD and TLD compared to CTR, with the BD group surpassing TLD (p = 0.0256). Immunohistochemical assessments revealed augmented NF-ĸB expression in the BD group in comparison to both CTR and TLD (p = 0.0006 and p = 0.0005). With this study we can conclude that BD induced acute pulmonary inflammation, whereas thalidomide manifested a notable capability in diminishing key inflammatory markers, indicating its prospective therapeutic significance in lung transplantation scenarios.
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Affiliation(s)
- Vanessa Sana Vilela
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Rua Dr. Eneas de Carvalho Aguiar 44, bloco 1, SS, sala 25, Cerqueira Cezar, Sao Paulo, SP, 05403-000, Brazil.
| | - Karina Andrighetti de Oliveira Braga
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Liliane Moreira Ruiz
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Natalia Aparecida Nepomuceno
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Paolo Oliveira Melo
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Giovana Maria Manzuti
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Vinícius Alcantara de Oliveira Costa
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Jhonatan de Campos Ramos
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Aristides Tadeu Correia
- Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Paulo Manuel Pêgo-Fernandes
- Departamento de Cardiopneumologia, Laboratorio de Pesquisa em Cirurgia Toracica, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
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5
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Bhattarai D, Lee SO, MacMillan-Crow LA, Parajuli N. Normal Proteasome Function Is Needed to Prevent Kidney Graft Injury during Cold Storage Followed by Transplantation. Int J Mol Sci 2024; 25:2147. [PMID: 38396827 PMCID: PMC10888692 DOI: 10.3390/ijms25042147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/02/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Kidney transplantation is the preferred treatment for end-stage kidney disease (ESKD). However, there is a shortage of transplantable kidneys, and donor organs can be damaged by necessary cold storage (CS). Although CS improves the viability of kidneys from deceased donors, prolonged CS negatively affects transplantation outcomes. Previously, we reported that renal proteasome function decreased after rat kidneys underwent CS followed by transplantation (CS + Tx). Here, we investigated the mechanism underlying proteasome dysfunction and the role of the proteasome in kidney graft outcome using a rat model of CS + Tx. We found that the key proteasome subunits β5, α3, and Rpt6 are modified, and proteasome assembly is impaired. Specifically, we detected the modification and aggregation of Rpt6 after CS + Tx, and Rpt6 modification was reversed when renal extracts were treated with protein phosphatases. CS + Tx kidneys also displayed increased levels of nitrotyrosine, an indicator of peroxynitrite (a reactive oxygen species, ROS), compared to sham. Because the Rpt6 subunit appeared to aggregate, we investigated the effect of CS + Tx-mediated ROS (peroxynitrite) generation on renal proteasome assembly and function. We treated NRK cells with exogenous peroxynitrite and evaluated PAC1 (proteasome assembly chaperone), Rpt6, and β5. Peroxynitrite induced a dose-dependent decrease in PAC1 and β5, but Rpt6 was not affected (protein level or modification). Finally, serum creatinine increased when we inhibited the proteasome in transplanted donor rat kidneys (without CS), recapitulating the effects of CS + Tx. These findings underscore the effects of CS + Tx on renal proteasome subunit dysregulation and also highlight the significance of proteasome activity in maintaining graft function following CS + Tx.
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Affiliation(s)
- Dinesh Bhattarai
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Seong-Ok Lee
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Lee Ann MacMillan-Crow
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Nirmala Parajuli
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Division of Nephrology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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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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7
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Poppelaars F, Eskandari SK, Damman J, Seelen MA, Faria B, Gaya da Costa M. A non-muscle myosin heavy chain 9 genetic variant is associated with graft failure following kidney transplantation. Kidney Res Clin Pract 2023; 42:389-402. [PMID: 37313613 PMCID: PMC10265209 DOI: 10.23876/j.krcp.22.061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 06/06/2022] [Accepted: 07/07/2022] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Despite current matching efforts to identify optimal donor-recipient pairs for kidney transplantation, alloimmunity remains a major source of late transplant failure. Additional genetic parameters in donor-recipient matching could help improve longterm outcomes. Here, we studied the impact of a non-muscle myosin heavy chain 9 gene (MYH9) polymorphism on allograft failure. METHODS We conducted an observational cohort study, analyzing the DNA of 1,271 kidney donor-recipient transplant pairs from a single academic hospital for the MYH9 rs11089788 C>A polymorphism. The associations of the MYH9 genotype with risk of graft failure, biopsy-proven acute rejection (BPAR), and delayed graft function (DGF) were estimated. RESULTS A trend was seen in the association between the MYH9 polymorphism in the recipient and graft failure (recessive model, p = 0.056), but not for the MYH9 polymorphism in the donor. The AA-genotype MYH9 polymorphism in recipients was associated with higher risk of DGF (p = 0.03) and BPAR (p = 0.021), although significance was lost after adjusting for covariates (p = 0.15 and p = 0.10, respectively). The combined presence of the MYH9 polymorphism in donor-recipient pairs was associated with poor long-term kidney allograft survival (p = 0.04), in which recipients with an AA genotype receiving a graft with an AA genotype had the worst outcomes. After adjustment, this combined genotype remained significantly associated with 15-year death-censored kidney graft survival (hazard ratio, 1.68; 95% confidence interval, 1.05-2.70; p = 0.03). CONCLUSION Our results reveal that recipients with an AA-genotype MYH9 polymorphism receiving a donor kidney with an AA genotype have significantly elevated risk of graft failure after kidney transplantation.
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Affiliation(s)
- Felix Poppelaars
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Siawosh K. Eskandari
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Jeffrey Damman
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Marc A. Seelen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Bernardo Faria
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Nephrology and Infectious Disease R&D Group, INEB, Institute of Investigation and Innovation in Health (i3S), University of Porto, Porto, Portugal
| | - Mariana Gaya da Costa
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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8
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Santarsiero D, Aiello S. The Complement System in Kidney Transplantation. Cells 2023; 12:cells12050791. [PMID: 36899927 PMCID: PMC10001167 DOI: 10.3390/cells12050791] [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: 01/02/2023] [Revised: 02/24/2023] [Accepted: 02/27/2023] [Indexed: 03/06/2023] Open
Abstract
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
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9
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Delaura IF, Gao Q, Anwar IJ, Abraham N, Kahan R, Hartwig MG, Barbas AS. Complement-targeting therapeutics for ischemia-reperfusion injury in transplantation and the potential for ex vivo delivery. Front Immunol 2022; 13:1000172. [PMID: 36341433 PMCID: PMC9626853 DOI: 10.3389/fimmu.2022.1000172] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 10/05/2022] [Indexed: 01/21/2023] Open
Abstract
Organ shortages and an expanding waitlist have led to increased utilization of marginal organs. All donor organs are subject to varying degrees of IRI during the transplant process. Extended criteria organs, including those from older donors and organs donated after circulatory death are especially vulnerable to ischemia-reperfusion injury (IRI). Involvement of the complement cascade in mediating IRI has been studied extensively. Complement plays a vital role in the propagation of IRI and subsequent recruitment of the adaptive immune elements. Complement inhibition at various points of the pathway has been shown to mitigate IRI and minimize future immune-mediated injury in preclinical models. The recent introduction of ex vivo machine perfusion platforms provides an ideal window for therapeutic interventions. Here we review the role of complement in IRI by organ system and highlight potential therapeutic targets for intervention during ex vivo machine preservation of donor organs.
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Affiliation(s)
- Isabel F. Delaura
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Qimeng Gao
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Imran J. Anwar
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Nader Abraham
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Riley Kahan
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
| | - Matthew G. Hartwig
- Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, United States
| | - Andrew S. Barbas
- Department of Surgery, Duke University School of Medicine, Durham, NC, United States
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10
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Fakhouri F, Schwotzer N, Golshayan D, Frémeaux-Bacchi V. The Rational Use of Complement Inhibitors in Kidney Diseases. Kidney Int Rep 2022; 7:1165-1178. [PMID: 35685323 PMCID: PMC9171628 DOI: 10.1016/j.ekir.2022.02.021] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/15/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
The development of complement inhibitors represented one of the major breakthroughs in clinical nephrology in the last decade. Complement inhibition has dramatically transformed the outcome of one of the most severe kidney diseases, the atypical hemolytic uremic syndrome (aHUS), a prototypic complement-mediated disorder. The availability of complement inhibitors has also opened new promising perspectives for the management of several other kidney diseases in which complement activation is involved to a variable extent. With the rapidly growing number of complement inhibitors tested in a rapidly increasing number of indications, a rational use of this innovative and expensive new therapeutic class has become crucial. The present review aims to summarize what we know, and what we still ignore, regarding complement activation and therapeutic inhibition in kidney diseases. It also provides some clues and elements of thoughts for a rational approach of complement modulation in kidney diseases.
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Affiliation(s)
- Fadi Fakhouri
- Service de Néphrologie et d'hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Nora Schwotzer
- Service de Néphrologie et d'hypertension, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Déla Golshayan
- Centre de Transplantation d'organes, Département de Médecine, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland
| | - Véronique Frémeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie, Paris University, Paris, France
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11
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Eerhart MJ, Reyes JA, Blanton CL, Danobeitia JS, Chlebeck PJ, Zitur LJ, Springer M, Polyak E, Coonen J, Capuano S, D’Alessandro AM, Torrealba J, van Amersfoort E, Ponstein Y, Van Kooten C, Burlingham W, Sullivan J, Pozniak M, Zhong W, Yankol Y, Fernandez LA. Complement Blockade in Recipients Prevents Delayed Graft Function and Delays Antibody-mediated Rejection in a Nonhuman Primate Model of Kidney Transplantation. Transplantation 2022; 106:60-71. [PMID: 34905763 PMCID: PMC8674492 DOI: 10.1097/tp.0000000000003754] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND Complement activation in kidney transplantation is implicated in the pathogenesis of delayed graft function (DGF). This study evaluated the therapeutic efficacy of high-dose recombinant human C1 esterase inhibitor (rhC1INH) to prevent DGF in a nonhuman primate model of kidney transplantation after brain death and prolonged cold ischemia. METHODS Brain death donors underwent 20 h of conventional management. Procured kidneys were stored on ice for 44-48 h, then transplanted into ABO-compatible major histocompatibility complex-mismatched recipients. Recipients were treated with vehicle (n = 5) or rhC1INH 500 U/kg plus heparin 40 U/kg (n = 8) before reperfusion, 12 h, and 24 h posttransplant. Recipients were followed up for 120 d. RESULTS Of vehicle-treated recipients, 80% (4 of 5) developed DGF versus 12.5% (1 of 8) rhC1INH-treated recipients (P = 0.015). rhC1INH-treated recipients had faster creatinine recovery, superior urinary output, and reduced urinary neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2-insulin-like growth factor-binding protein 7 throughout the first week, indicating reduced allograft injury. Treated recipients presented lower postreperfusion plasma interleukin (IL)-6, IL-8, tumor necrosis factor-alpha, and IL-18, lower day 4 monocyte chemoattractant protein 1, and trended toward lower C5. Treated recipients exhibited less C3b/C5b-9 deposition on day 7 biopsies. rhC1INH-treated animals also trended toward prolonged mediated rejection-free survival. CONCLUSIONS Our results recommend high-dose C1INH complement blockade in transplant recipients as an effective strategy to reduce kidney injury and inflammation, prevent DGF, delay antibody-mediated rejection development, and improve transplant outcomes.
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Affiliation(s)
- Michael J. Eerhart
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jose A. Reyes
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- Department of Surgery, New York Medical College at Metropolitan Hospital Center, New York, NY, United States
| | - Casi L. Blanton
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Juan S. Danobeitia
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Peter J. Chlebeck
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Laura J. Zitur
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Megan Springer
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Erzsebet Polyak
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jennifer Coonen
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States
| | - Saverio Capuano
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, United States
| | - Anthony M. D’Alessandro
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jose Torrealba
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | | | | | - Cees Van Kooten
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - William Burlingham
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Jeremy Sullivan
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Myron Pozniak
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Weixiong Zhong
- Department of Pathology, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Yucel Yankol
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Luis A. Fernandez
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
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12
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See Hoe LE, Wildi K, Obonyo NG, Bartnikowski N, McDonald C, Sato K, Heinsar S, Engkilde-Pedersen S, Diab S, Passmore MR, Wells MA, Boon AC, Esguerra A, Platts DG, James L, Bouquet M, Hyslop K, Shuker T, Ainola C, Colombo SM, Wilson ES, Millar JE, Malfertheiner MV, Reid JD, O'Neill H, Livingstone S, Abbate G, Sato N, He T, von Bahr V, Rozencwajg S, Byrne L, Pimenta LP, Marshall L, Nair L, Tung JP, Chan J, Haqqani H, Molenaar P, Li Bassi G, Suen JY, McGiffin DC, Fraser JF. A clinically relevant sheep model of orthotopic heart transplantation 24 h after donor brainstem death. Intensive Care Med Exp 2021; 9:60. [PMID: 34950993 PMCID: PMC8702587 DOI: 10.1186/s40635-021-00425-4] [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: 07/28/2021] [Accepted: 11/23/2021] [Indexed: 11/10/2022] Open
Abstract
Background Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD.
Methods BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for 6 h. Donor and recipient blood were assayed for inflammatory and cardiac injury markers, and cardiac function was assessed using echocardiography. Repeated measurements between the two different groups during the study observation period were assessed by mixed ANOVA for repeated measures.
Results Brainstem death caused an immediate catecholaminergic hemodynamic response (mean arterial pressure, p = 0.09), systemic inflammation (IL-6 - p = 0.025, IL-8 - p = 0.002) and cardiac injury (cardiac troponin I, p = 0.048), requiring vasopressor support (vasopressor dependency index, VDI, p = 0.023), with normalisation of biomarkers and physiology over 24 h. All hearts were weaned from CPB and monitored for 6 h post-HTx, except one (sham) recipient that died 2 h post-HTx. Hemodynamic (VDI - p = 0.592, heart rate - p = 0.747) and metabolic (blood lactate, p = 0.546) parameters post-HTx were comparable between groups, despite the observed physiological perturbations that occurred during donor BSD. All p values denote interaction among groups and time in the ANOVA for repeated measures. Conclusions We have successfully developed an ovine HTx model following 24 h of donor BSD. After 6 h of critical care management post-HTx, there were no differences between groups, despite evident hemodynamic perturbations, systemic inflammation, and cardiac injury observed during donor BSD. This preclinical model provides a platform for critical assessment of injury development pre- and post-HTx, and novel therapeutic evaluation. Supplementary Information The online version contains supplementary material available at 10.1186/s40635-021-00425-4.
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Affiliation(s)
- Louise E See Hoe
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia. .,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia. .,School of Pharmacy and Medical Sciences, Griffith University, Southport, QLD, Australia.
| | - Karin Wildi
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Cardiovascular Research Institute Basel, Basel, Switzerland
| | - Nchafatso G Obonyo
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Wellcome Trust Centre for Global Health Research, Imperial College London, London, UK.,Initiative to Develop African Research Leaders (IDeAL), Kilifi, Kenya
| | - Nicole Bartnikowski
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane, QLD, Australia
| | - Charles McDonald
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Department of Anaesthesia and Perfusion, The Prince Charles Hospital, Chermside, QLD, Australia
| | - Kei Sato
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Silver Heinsar
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Second Department of Intensive Care, North Estonia Medical Centre, Tallinn, Estonia
| | - Sanne Engkilde-Pedersen
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Research and Development, Australian Red Cross Lifeblood, Brisbane, QLD, Australia
| | - Sara Diab
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Margaret R Passmore
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Matthew A Wells
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,School of Pharmacy and Medical Sciences, Griffith University, Southport, QLD, Australia
| | - Ai-Ching Boon
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Arlanna Esguerra
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Research and Development, Australian Red Cross Lifeblood, Brisbane, QLD, Australia
| | - David G Platts
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Lynnette James
- Department of Cardiac Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Mahe Bouquet
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Kieran Hyslop
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Tristan Shuker
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Carmen Ainola
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Sebastiano M Colombo
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Milan, Italy
| | - Emily S Wilson
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Jonathan E Millar
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Roslin Institute, University of Edinburgh, Edinburgh, UK
| | - Maximillian V Malfertheiner
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Department of Internal Medicine II, Cardiology and Pneumology, University Medical Center Regensburg, Regensburg, Germany
| | - Janice D Reid
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Hollier O'Neill
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Samantha Livingstone
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Gabriella Abbate
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Noriko Sato
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Ting He
- Department of Cardiac Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Viktor von Bahr
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sacha Rozencwajg
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Pitié-Salpêtrière University Hospital, Paris, France
| | - Liam Byrne
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,The Canberra Hospital Intensive Care, Garran, ACT, Australia.,Australia National University, Canberra, ACT, Australia
| | - Leticia P Pimenta
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia
| | - Lachlan Marshall
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Department of Cardiac Surgery, Princess Alexandra Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital, Brisbane, QLD, Australia
| | - Lawrie Nair
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital, Brisbane, QLD, Australia
| | - John-Paul Tung
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Research and Development, Australian Red Cross Lifeblood, Brisbane, QLD, Australia.,Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Jonathan Chan
- Prince Charles Hospital, Brisbane, QLD, Australia.,School of Medicine, Griffith University, Southport, QLD, Australia
| | - Haris Haqqani
- Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Prince Charles Hospital, Brisbane, QLD, Australia
| | - Peter Molenaar
- Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Gianluigi Li Bassi
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Barcelona, Spain
| | - Jacky Y Suen
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.,School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - David C McGiffin
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Cardiothoracic Surgery and Transplantation, The Alfred Hospital, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
| | - John F Fraser
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, QLD, Australia.,Prince Charles Hospital Northside Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
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13
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Freiwald T, Afzali B. Renal diseases and the role of complement: Linking complement to immune effector pathways and therapeutics. Adv Immunol 2021; 152:1-81. [PMID: 34844708 PMCID: PMC8905641 DOI: 10.1016/bs.ai.2021.09.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The complement system is an ancient and phylogenetically conserved key danger sensing system that is critical for host defense against pathogens. Activation of the complement system is a vital component of innate immunity required for the detection and removal of pathogens. It is also a central orchestrator of adaptive immune responses and a constituent of normal tissue homeostasis. Once complement activation occurs, this system deposits indiscriminately on any cell surface in the vicinity and has the potential to cause unwanted and excessive tissue injury. Deposition of complement components is recognized as a hallmark of a variety of kidney diseases, where it is indeed associated with damage to the self. The provenance and the pathophysiological role(s) played by complement in each kidney disease is not fully understood. However, in recent years there has been a renaissance in the study of complement, with greater appreciation of its intracellular roles as a cell-intrinsic system and its interplay with immune effector pathways. This has been paired with a profusion of novel therapeutic agents antagonizing complement components, including approved inhibitors against complement components (C)1, C3, C5 and C5aR1. A number of clinical trials have investigated the use of these more targeted approaches for the management of kidney diseases. In this review we present and summarize the evidence for the roles of complement in kidney diseases and discuss the available clinical evidence for complement inhibition.
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Affiliation(s)
- Tilo Freiwald
- Immunoregulation Section, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, United States; Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany
| | - Behdad Afzali
- Department of Nephrology, University Hospital Frankfurt, Goethe-University, Frankfurt am Main, Germany.
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14
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Pajenda S, Zawedde F, Kapps S, Wagner L, Schmidt A, Winnicki W, O’Connell D, Gerges D. Urinary C3 levels associated with sepsis and acute kidney injury-A pilot study. PLoS One 2021; 16:e0259777. [PMID: 34767613 PMCID: PMC8589214 DOI: 10.1371/journal.pone.0259777] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 10/18/2021] [Indexed: 12/01/2022] Open
Abstract
Acute kidney injury (AKI) is an abrupt deterioration of renal function often caused by severe clinical disease such as sepsis, and patients require intensive care. Acute-phase parameters for systemic inflammation are well established and used in routine clinical diagnosis, but no such parameters are known for AKI and inflammation at the local site of tissue damage, namely the nephron. Therefore, we sought to investigate complement factors C3a/C3 in urine and urinary sediment cells. After the development of a C3a/C3-specific mouse monoclonal antibody (3F7E2), urine excretion from ICU sepsis patients was examined by dot blot and immunoblotting. This C3a/C3 ELISA and a C3a ELISA were used to obtain quantitative data over 24 hours for 6 consecutive days. Urine sediment cells were analyzed for topology of expression. Patients with severe infections (n = 85) showed peak levels of C3a/C3 on the second day of ICU treatment. The majority (n = 59) showed C3a/C3 levels above 20 μg/ml at least once in the first 6 days after admission. C3a was detectable on all 6 days. Peak C3a/C3 levels correlated negatively with peak C-reactive protein (CRP) levels. No relationship was found between peak C3a/C3 with peak leukocyte count, age, or AKI stage. Analysis of urine sediment cells identified C3a/C3-producing epithelial cells with reticular staining patterns and cells with large-granular staining. Opsonized bacteria were detected in patients with urinary tract infections. In critically ill sepsis patients with AKI, urinary C3a/C3 inversely correlated with serum CRP. Whether urinary C3a/C3 has a protective function through autophagy, as previously shown for cisplatin exposure, or is a by-product of sepsis caused by pathogenic stimuli to the kidney must remain open in this study. However, our data suggest that C3a/C3 may function as an inverse acute-phase parameter that originates in the kidney and is detectable in urine.
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Affiliation(s)
- Sahra Pajenda
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Florence Zawedde
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Sebastian Kapps
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Ludwig Wagner
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alice Schmidt
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Winnicki
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - David O’Connell
- School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin, Ireland
| | - Daniela Gerges
- Division of Nephrology and Dialysis, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
- * E-mail:
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15
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Walweel K, Boon AC, See Hoe LE, Obonyo NG, Pedersen SE, Diab SD, Passmore MR, Hyslop K, Colombo SM, Bartnikowski NJ, Bouquet M, Wells MA, Black DM, Pimenta LP, Stevenson AK, Bisht K, Skeggs K, Marshall L, Prabhu A, James LN, Platts DG, Macdonald PS, McGiffin DC, Suen JY, Fraser JF. Brain stem death induces pro-inflammatory cytokine production and cardiac dysfunction in sheep model. Biomed J 2021; 45:776-787. [PMID: 34666219 PMCID: PMC9661508 DOI: 10.1016/j.bj.2021.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 08/12/2021] [Accepted: 10/07/2021] [Indexed: 11/23/2022] Open
Abstract
Introduction Organs procured following brain stem death (BSD) are the main source of organ grafts for transplantation. However, BSD is associated with inflammatory responses that may damage the organ and affect both the quantity and quality of organs available for transplant. Therefore, we aimed to investigate plasma and bronchoalveolar lavage (BAL) pro-inflammatory cytokine profiles and cardiovascular physiology in a clinically relevant 6-h ovine model of BSD. Methods Twelve healthy female sheep (37–42 Kg) were anaesthetized and mechanically ventilated prior to undergoing BSD induction and then monitored for 6 h. Plasma and BAL endothelin-1 and cytokines (IL-1β, 6, 8 and tumour necrosis factor alpha (TNF-α)) were assessed by ELISA. Differential white blood cell counts were performed. Cardiac function during BSD was also examined using echocardiography, and cardiac biomarkers (A-type natriuretic peptide and troponin I were measured in plasma. Results Plasma concentrations big ET-1, IL-6, IL-8, TNF-α and BAL IL-8 were significantly (p < 0.01) increased over baseline at 6 h post-BSD. Increased numbers of neutrophils were observed in the whole blood (3.1 × 109 cells/L [95% confidence interval (CI) 2.06–4.14] vs. 6 × 109 cells/L [95%CI 3.92–7.97]; p < 0.01) and BAL (4.5 × 109 cells/L [95%CI 0.41–9.41] vs. 26 [95%CI 12.29–39.80]; p = 0.03) after 6 h of BSD induction vs baseline. A significant increase in ANP production (20.28 pM [95%CI 16.18–24.37] vs. 78.68 pM [95%CI 53.16–104.21]; p < 0.0001) and cTnI release (0.039 ng/mL vs. 4.26 [95%CI 2.69–5.83] ng/mL; p < 0.0001), associated with a significant reduction in heart contractile function, were observed between baseline and 6 h. Conclusions BSD induced systemic pro-inflammatory responses, characterized by increased neutrophil infiltration and cytokine production in the circulation and BAL fluid, and associated with reduced heart contractile function in ovine model of BSD.
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Affiliation(s)
- K Walweel
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia.
| | - A C Boon
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - L E See Hoe
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - N G Obonyo
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; Initiative to Develop African Research Leaders, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
| | - S E Pedersen
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - S D Diab
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - M R Passmore
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - K Hyslop
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - S M Colombo
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; University of Milan, Italy
| | | | - M Bouquet
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - M A Wells
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; School of Medical Science, Griffith University, Australia
| | - D M Black
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - L P Pimenta
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - A K Stevenson
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - K Bisht
- Mater Research Institute, University of Queensland, Australia
| | - K Skeggs
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia; Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
| | - L Marshall
- Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
| | - A Prabhu
- The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - L N James
- Princess Alexandra Hospital, Woolloongabba, Brisbane, Australia
| | - D G Platts
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia
| | - P S Macdonald
- Cardiac Mechanics Research Laboratory, St. Vincent's Hospital and the Victor Chang Cardiac Research Institute, Victoria Street, Darlinghurst, Sydney, Australia
| | - D C McGiffin
- Cardiothoracic Surgery and Transplantation, The Alfred Hospital, Melbourne, Australia
| | - J Y Suen
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia.
| | - J F Fraser
- Critical Care Research Group, Level 3, Clinical Sciences Building, The Prince Charles Hospital, Rode Road, Brisbane, Australia.
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16
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Armstrong-Jr R, Ricardo-da-Silva FY, Vidal-Dos-Santos M, Correia CDJ, Anunciação LF, Coutinho E Silva RDS, Moreira LFP, Leuvenink HGD, Breithaupt-Faloppa AC. Protective role of 17β-estradiol treatment in renal injury on female rats submitted to brain death. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1125. [PMID: 34430566 PMCID: PMC8350685 DOI: 10.21037/atm-21-1408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/03/2021] [Indexed: 12/04/2022]
Abstract
Background Clinical and experimental data highlight the consequences of brain death on the quality of organs and demonstrate the importance of donor state to the results of transplantation. Female rats show higher cardio-pulmonary injury linked to decreased concentrations of female sex hormones after brain-dead (BD). This study evaluated the effect of 17β-estradiol on brain death induced renal injury in female rats. Methods Female Wistar rats were randomically allocated into 4 groups: false-operation (Sham), BD, treatment with 17β-estradiol (50 µg/mL, 2 mL/h) 3 h after brain death (E2-T3), or immediately after brain death confirmation (E2-T0). Creatinine, urea, cytokines, and complement system components were quantified. Renal injury markers, such as KIM-1, Caspase-3, BCL-2 and MMP2/9 were evaluated. Results Brain death leads to increased kidney KIM-1 expression and longer 17β-estradiol treatment resulted in downregulation (P<0.0001). There was increase of neutrophil numbers in kidney from BD rats and E2 treatment was able to reduce it (P=0.018). Regarding complement elements, E2-T3 group evidenced E2 therapeutic effects, reducing C5b-9 (P=0.0004), C3aR (P=0.054) and C5aR (P=0.019). In parallel, there were 17β-estradiol effects in reducing MMP2 (P=0.0043), MMP9 (P=0.011), and IL-6 (P=0.024). Moreover, E2-T3 group improved renal function in comparison to BD group (P=0.0938). Conclusions 17β-estradiol treatment was able to reduce acute kidney damage in BD female rats owing to its ability to prevent tissue damage, formation of C5b-9, and local synthesis of inflammatory mediators.
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Affiliation(s)
- Roberto Armstrong-Jr
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Fernanda Yamamoto Ricardo-da-Silva
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Marina Vidal-Dos-Santos
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Cristiano de Jesus Correia
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Lucas Ferreira Anunciação
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Raphael Dos Santos Coutinho E Silva
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Luiz Felipe Pinho Moreira
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Henri Gerrit Derk Leuvenink
- Department of Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Ana Cristina Breithaupt-Faloppa
- Laboratorio de Cirurgia Cardiovascular e Fisiopatologia da Circulação (LIM-11), Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Lei B, Sleiman MM, Cheng Q, Tu Z, Zhu P, Goddard M, Martins PN, Langerude L, Nadig S, Tomlinson S, Atkinson C. In Situ Pre-Treatment of Vascularized Composite Allografts With a Targeted Complement Inhibitor Protects Against Brain Death and Ischemia Reperfusion Induced Injuries. Front Immunol 2021; 12:630581. [PMID: 34394069 PMCID: PMC8358649 DOI: 10.3389/fimmu.2021.630581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 06/14/2021] [Indexed: 12/12/2022] Open
Abstract
Introduction Donor brain death (BD) is an unavoidable component of vascularized composite allograft (VCA) transplantation and a key contributor to ischemia-reperfusion injury (IRI). Complement is activated and deposited within solid organ grafts as a consequence of BD and has been shown to exacerbate IRI, although the role of BD and complement in VCA and the role it plays in IRI and VCA rejection has not been studied. Methods BD was induced in Balb/c donors, and the VCA perfused prior to graft procurement with UW solution supplemented with or without CR2-Crry, a C3 convertase complement inhibitor that binds at sites of complement activation, such as that induced on the endothelium by induction of BD. Following perfusion, donor VCAs were cold stored for 6 hours before transplantation into C57BL/6 recipients. Donor VCAs from living donors (LD) were also procured and stored. Analyses included CR2-Crry graft binding, complement activation, toxicity, injury/inflammation, graft gene expression and survival. Results Compared to LD VCAs, BD donor VCAs had exacerbated IRI and rejected earlier. Following pretransplant in-situ perfusion of the donor graft, CR2-Crry bound within the graft and was retained post-transplantation. CR2-Crry treatment significantly reduced complement deposition, inflammation and IRI as compared to vehicle-treated BD donors. Treatment of BD donor VCAs with CR2-Crry led to an injury profile not dissimilar to that seen in recipients of LD VCAs. Conclusion Pre-coating a VCA with CR2-Crry in a clinically relevant treatment paradigm provides localized, and therefore minimally immunosuppressive, protection from the complement-mediated effects of BD induced exacerbated IRI.
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Affiliation(s)
- Biao Lei
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - M. Mahdi Sleiman
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Qi Cheng
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Institute of Organ Transplantation, Huazhong University of Science and Technology, Wuhan, China
| | - Zhenxiao Tu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Department of Surgery, Hepatic and Vascular Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peng Zhu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Department of Surgery, Hepatic and Vascular Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Martin Goddard
- Pathology Department, Papworth Hospital NHS Trust, Cambridge, United Kingdom
| | - Paulo N. Martins
- UMass Memorial Medical Center, Department of Surgery, Transplant Division, University of Massachusetts, Worcester, MA, United States
| | - Logan Langerude
- Division of Pulmonary Medicine, University of Florida, Gainesville, FL, United States
| | - Satish Nadig
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Department of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, SC, United States
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Department of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, SC, United States
- Ralph H. Johnson VA Medical Center, Charleston, SC, United States
| | - Carl Atkinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States
- Division of Pulmonary Medicine, University of Florida, Gainesville, FL, United States
- Department of Surgery, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, Microbiology and Immunology, Charleston, SC, United States
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Multiplex gene analysis reveals T-cell and antibody-mediated rejection-specific upregulation of complement in renal transplants. Sci Rep 2021; 11:15464. [PMID: 34326417 PMCID: PMC8322413 DOI: 10.1038/s41598-021-94954-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 07/13/2021] [Indexed: 01/03/2023] Open
Abstract
In renal transplantation, complement is involved in ischemia reperfusion injury, graft rejection and dysfunction. However, it is still unclear how induction of complement and its activation are initiated. Using allograft biopsies of a well-characterized cohort of 28 renal transplant patients with no rejection (Ctrl), delayed graft function (DGF), acute T-cell-mediated (TCMR) or antibody-mediated rejection (ABMR) we analyzed differences in complement reaction. For that mRNA was isolated from FFPE sections, quantified with a multiplex gene expression panel and correlated with transplant conditions and follow-up of patients. Additionally, inflammatory cells were quantified by multiplex immunohistochemistry. In allograft biopsies with TCMR and ABMR gene expression of C1QB was 2-4 fold elevated compared to Ctrl. In TCMR biopsies, mRNA counts of several complement-related genes including C1S, C3, CFB and complement regulators CFH, CR1 and SERPING1 were significantly increased compared to Ctrl. Interestingly, expression levels of about 75% of the analyzed complement related genes correlated with cold ischemia time (CIT) and markers of inflammation. In conclusion, this study suggest an important role of complement in transplant pathology which seems to be at least in part triggered by CIT. Multiplex mRNA analysis might be a useful method to refine diagnosis and explore new pathways involved in rejection.
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The Influence of Donor and Recipient Complement C3 Polymorphisms on Liver Transplant Outcome. Int J Hepatol 2021; 2021:6636456. [PMID: 34123432 PMCID: PMC8168477 DOI: 10.1155/2021/6636456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/27/2021] [Indexed: 12/19/2022] Open
Abstract
Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P = 0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P = 0.018), of retransplantation on rejection risk (hazard ratio 6.3, P = 0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P = 0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.
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Kielar M, Gala-Błądzińska A, Dumnicka P, Ceranowicz P, Kapusta M, Naumnik B, Kubiak G, Kuźniewski M, Kuśnierz-Cabala B. Complement Components in the Diagnosis and Treatment after Kidney Transplantation-Is There a Missing Link? Biomolecules 2021; 11:biom11060773. [PMID: 34064132 PMCID: PMC8224281 DOI: 10.3390/biom11060773] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 12/25/2022] Open
Abstract
Currently, kidney transplantation is widely accepted as the renal replacement therapy allowing for the best quality of life and longest survival of patients developing end-stage renal disease. However, chronic transplant rejection, recurrence of previous kidney disease or newly acquired conditions, or immunosuppressive drug toxicity often lead to a deterioration of kidney allograft function over time. Complement components play an important role in the pathogenesis of kidney allograft impairment. Most studies on the role of complement in kidney graft function focus on humoral rejection; however, complement has also been associated with cell mediated rejection, post-transplant thrombotic microangiopathy, the recurrence of several glomerulopathies in the transplanted kidney, and transplant tolerance. Better understanding of the complement involvement in the transplanted kidney damage has led to the development of novel therapies that inhibit complement components and improve graft survival. The analysis of functional complotypes, based on the genotype of both graft recipient and donor, may become a valuable tool for assessing the risk of acute transplant rejection. The review summarizes current knowledge on the pathomechanisms of complement activation following kidney transplantation and the resulting diagnostic and therapeutic possibilities.
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Affiliation(s)
- Małgorzata Kielar
- St. Louis Regional Children’s Hospital, Medical Diagnostic Laboratory with a Bacteriology Laboratory, Strzelecka 2 St., 31-503 Kraków, Poland;
| | - Agnieszka Gala-Błądzińska
- Medical College of Rzeszów University, Institute of Medical Sciences, Kopisto 2A Avn., 35-310 Rzeszów, Poland;
| | - Paulina Dumnicka
- Jagiellonian University Medical College, Faculty of Pharmacy, Department of Medical Diagnostics, Medyczna 9 St., 30-688 Kraków, Poland;
| | - Piotr Ceranowicz
- Jagiellonian University Medical College, Faculty of Medicine, Department of Physiology, Grzegórzecka 16 St., 31-531 Kraków, Poland;
| | - Maria Kapusta
- Jagiellonian University Medical College, Faculty of Medicine, Chair of Clinical Biochemistry, Department of Diagnostics, Kopernika 15A St., 31-501 Kraków, Poland;
| | - Beata Naumnik
- Medical University of Białystok, Faculty of Medicine, 1st Department of Nephrology and Transplantation with Dialysis Unit, Żurawia 14 St., 15-540 Białystok, Poland;
| | - Grzegorz Kubiak
- Catholic University of Leuven, Department of Cardiovascular Diseases, 3000 Leuven, Belgium;
| | - Marek Kuźniewski
- Jagiellonian University Medical College, Faculty of Medicine, Chair and Department of Nephrology, Jakubowskiego 2 St., 30-688 Kraków, Poland;
| | - Beata Kuśnierz-Cabala
- Jagiellonian University Medical College, Faculty of Medicine, Chair of Clinical Biochemistry, Department of Diagnostics, Kopernika 15A St., 31-501 Kraków, Poland;
- Correspondence: ; Tel.: +48-12-424-83-65
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21
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Halpern SE, Rush CK, Edwards RW, Brennan TV, Barbas AS, Pollara J. Systemic Complement Activation in Donation After Brain Death Versus Donation After Circulatory Death Organ Donors. EXP CLIN TRANSPLANT 2021; 19:635-644. [PMID: 33877036 DOI: 10.6002/ect.2020.0425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Complement activation in organs from deceased donors is associated with allograft injury and acute rejection. Because use of organs from donors after circulatory death is increasing, we characterized relative levels of complement activation in organs from donors after brain death and after circulatory death and examined associations between donor complement factor levels and outcomes after kidney and liver transplant. MATERIALS AND METHODS Serum samples from 65 donors (55 donations after brain death, 10 donations after circulatory death) were analyzed for classical, lectin, alternative, and terminal pathway components by Luminex multiplex assays. Complement factor levels were compared between groups, and associations with posttransplant outcomes were explored. RESULTS Serum levels of the downstream complement activation product C5a were similar in organs from donors after circulatory death versus donors after brain death. In organs from donors after circulatory death, complement activation occurred primarily via the alternative pathway; the classical, lectin, and alternative pathways all contributed in organs from donors after brain death. Donor complement levels were not associated with outcomes after kidney transplant. Lower donor complement levels were associated with need for transfusion, reintervention, hospital readmission, and acute rejection after liver transplant. CONCLUSIONS Complement activation occurs at similar levels in organs donated from donors after circulatory death versus those after brain death. Lower donor complement levels may contribute to adverse outcomes after liver transplant. Further study is warranted to better understand how donor complement activation contributes to posttransplant outcomes.
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Affiliation(s)
- Samantha E Halpern
- From the School of Medicine, Duke University, Durham, North Carolina, USA
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22
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Ávila A, Gavela E, Sancho A. Thrombotic Microangiopathy After Kidney Transplantation: An Underdiagnosed and Potentially Reversible Entity. Front Med (Lausanne) 2021; 8:642864. [PMID: 33898482 PMCID: PMC8063690 DOI: 10.3389/fmed.2021.642864] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/22/2021] [Indexed: 01/25/2023] Open
Abstract
Thrombotic microangiopathy is a rare but serious complication that affects kidney transplant recipients. It appears in 0.8–14% of transplanted patients and negatively affects graft and patient survival. It can appear in a systemic form, with hemolytic microangiopathic anemia, thrombocytopenia, and renal failure, or in a localized form, with progressive renal failure, proteinuria, or arterial hypertension. Post-transplant thrombotic microangiopathy is classified as recurrent atypical hemolytic uremic syndrome or de novo thrombotic microangiopathy. De novo thrombotic microangiopathy accounts for the majority of cases. Distinguishing between the 2 conditions can be difficult, given there is an overlap between them. Complement overactivation is the cornerstone of all post-transplant thrombotic microangiopathies, and has been demonstrated in the context of organ procurement, ischemia-reperfusion phenomena, immunosuppressive drugs, antibody-mediated rejection, viral infections, and post-transplant relapse of antiphospholipid antibody syndrome. Although treatment of the causative agents is usually the first line of treatment, this approach might not be sufficient. Plasma exchange typically resolves hematologic abnormalities but does not improve renal function. Complement blockade with eculizumab has been shown to be an effective therapy in post-transplant thrombotic microangiopathy, but it is necessary to define which patients can benefit from this therapy and when and how eculizumab should be used.
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Affiliation(s)
- Ana Ávila
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
| | - Eva Gavela
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
| | - Asunción Sancho
- Nephrology Department, University Hospital Dr. Peset, Valencia, Spain
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23
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van Zanden JE, Jager NM, Seelen MA, Daha MR, Veldhuis ZJ, Leuvenink HG, Erasmus ME. Brain death-induced lung injury is complement dependent, with a primary role for the classical/lectin pathway. Am J Transplant 2021; 21:993-1002. [PMID: 32743873 PMCID: PMC7984080 DOI: 10.1111/ajt.16231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 07/20/2020] [Accepted: 07/20/2020] [Indexed: 01/25/2023]
Abstract
In brain-dead donors immunological activation occurs, which deteriorates donor lung quality. Whether the complement system is activated and which pathways are herein involved, remain unknown. We aimed to investigate whether brain death (BD)-induced lung injury is complement dependent and dissected the contribution of the complement activation pathways. BD was induced and sustained for 3 hours in wild-type (WT) and complement deficient mice. C3-/- mice represented total complement deficiency, C4-/- mice represented deficiency of the classical and lectin pathway, and factor properdin (P)-/- mice represented alternative pathway deficiency. Systemic and local complement levels, histological lung injury, and pulmonary inflammation were assessed. Systemic and local complement levels were reduced in C3-/- mice. In addition, histological lung injury and inflammation were attenuated, as corroborated by influx of neutrophils and gene expressions of interleukin (IL)-6, IL-8-like KC, TNF-α, E-selectin, and MCP-1. In C4-/- mice, complement was reduced on both systemic and local levels and histological lung injury and inflammatory status were ameliorated. In P-/- mice, histological lung injury was attenuated, though systemic and local complement levels, IL-6 and KC gene expressions, and neutrophil influx were not affected. We demonstrated that BD-induced lung injury is complement dependent, with a primary role for the classical/lectin activation pathway.
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Affiliation(s)
- Judith E. van Zanden
- Department of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Neeltina M. Jager
- Department of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Marc A. Seelen
- Division of NephrologyDepartment of Internal MedicineUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Mohamed R. Daha
- Division of NephrologyDepartment of Internal MedicineUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands,Department of NephrologyLeiden University Medical CenterLeidenthe Netherlands
| | - Zwanida J. Veldhuis
- Department of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Henri G.D. Leuvenink
- Department of SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Michiel E. Erasmus
- Department of Cardiothoracic SurgeryUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
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Comparative Analysis of Risk Factors in Declined Kidneys from Donation after Brain Death and Circulatory Death. ACTA ACUST UNITED AC 2020; 56:medicina56060317. [PMID: 32604873 PMCID: PMC7353903 DOI: 10.3390/medicina56060317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/17/2020] [Accepted: 06/18/2020] [Indexed: 01/10/2023]
Abstract
Background and objectives: Kidneys from donation after circulatory death (DCD) are more likely to be declined for transplantation compared with kidneys from donation after brain death (DBD). The aim of this study was to evaluate characteristics in the biopsies of human DCD and DBD kidneys that were declined for transplantation in order to rescue more DCD kidneys. Materials and Methods: Sixty kidney donors (DCD = 36, DBD = 24) were recruited into the study and assessed using donor demographics. Kidney biopsies taken post cold storage were also evaluated for histological damage, inflammation (myeloperoxidase, MPO), von Willebrand factor (vWF) expression, complement 4d (C4d) deposition and complement 3 (C3) activation using H&E and immunohistochemistry staining, and Western blotting. Results: More DBD donors (16/24) had a history of hypertension compared with DCDs (8/36, p = 0.001). The mean warm ischemic time in the DCD kidneys was 12.9 ± 3.9 min. The mean cold ischemic time was not significantly different between the two groups of kidney donors (DBD 33.3 ± 16.7 vs. DCD 28.6 ± 14.1 h, p > 0.05). The score of histological damage and MPO, as well as the reactivity of vWF, C4d and C3, varied between kidneys, but there was no significant difference between the two donor types (p > 0.05). However, vWF reactivity might be an early indicator for loss of tissue integrity, while C4d deposition and activated C3 might be better predictors for histological damage. Conclusions: Similar characteristics of DCD were shown in comparison with DBD kidneys. Importantly, the additional warm ischemic time in DCD appeared to have no further detectable adverse effects on tissue injury, inflammation and complement activation. vWF, C4d and C3 might be potential biomarkers facilitating the evaluation of donor kidneys.
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Brain Death Enhances Activation of the Innate Immune System and Leads to Reduced Renal Metabolic Gene Expression. Transplantation 2020; 103:1821-1833. [PMID: 30964836 DOI: 10.1097/tp.0000000000002744] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Brain death (BD)-associated inflammation has been implicated in decreased kidney allograft function and survival, but the underlying mechanisms have not been well distinguished from the conditions of critical care itself. We have developed a clinically translatable model to separate and investigate strategies to improve donor management and critical care. METHODS Brain-dead (n = 12) and sham (n = 5) rhesus macaques were maintained for 20 hours under intensive care unit-level conditions. Samples were collected for immunophenotyping, analysis of plasma proteins, coagulation studies, and gene analysis for changes in immune and metabolic profile with comparison to naive samples (n = 10). RESULTS We observed an increase in circulating leukocytes and cytokines, activation of complement and coagulation pathways, and upregulation of genes associated with inflammation in both brain-dead and sham subjects relative to naïve controls. Sham demonstrated an intermediate phenotype of inflammation compared to BD. Analysis of gene expression in kidneys from BD kidneys revealed a similar upregulation of inflammatory profile in both BD and sham subjects, but BD presented a distinct reduction in metabolic and respiratory processes compared to sham and naïve kidneys. CONCLUSION BD is associated with activation of specific pathways of the innate immune system and changes to metabolic gene expression in renal tissue itself; however, sham donors presented an intermediate inflammatory response attributable to the critical care environment. The early onset and penetrating impact of this inflammatory response underscores the need for early intervention to prevent perioperative tissue injury to transplantable organs.
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Danobeitia JS, Zens TJ, Chlebeck PJ, Zitur LJ, Reyes JA, Eerhart MJ, Coonen J, Capuano S, D’Alessandro AM, Torrealba JR, Burguete D, Brunner K, Amersfoort E, Ponstein-Simarro Doorten Y, Van Kooten C, Jankowska-Gan E, Burlingham W, Sullivan J, Djamali A, Pozniak M, Yankol Y, Fernandez LA. Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation. Am J Transplant 2020; 20:1513-1526. [PMID: 31922336 PMCID: PMC7261643 DOI: 10.1111/ajt.15777] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 12/05/2019] [Accepted: 12/22/2019] [Indexed: 01/25/2023]
Abstract
Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 - vehicle, G2 - rhC1INH+heparin, and G3 - heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase-associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation.
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Affiliation(s)
- Juan S. Danobeitia
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Tiffany J. Zens
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Peter J. Chlebeck
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Laura J. Zitur
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jose A. Reyes
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Michael J. Eerhart
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jennifer Coonen
- Wisconsin Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Saverio Capuano
- Wisconsin Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin
| | - Anthony M. D’Alessandro
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jose R. Torrealba
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Daniel Burguete
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kevin Brunner
- Wisconsin Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin
| | | | | | - Cees Van Kooten
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ewa Jankowska-Gan
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - William Burlingham
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Jeremy Sullivan
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Arjang Djamali
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Myron Pozniak
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Yucel Yankol
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Luis A. Fernandez
- Department of Surgery, Division of Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
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27
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Bera KD, Shah A, English MR, Harvey D, Ploeg RJ. Optimisation of the organ donor and effects on transplanted organs: a narrative review on current practice and future directions. Anaesthesia 2020; 75:1191-1204. [PMID: 32430910 DOI: 10.1111/anae.15037] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2020] [Indexed: 12/16/2022]
Abstract
Mortality remains high for patients on the waiting list for organ transplantation. A marked imbalance between the number of available organs and recipients that need to be transplanted persists. Organs from deceased donors are often declined due to perceived and actual suboptimal quality. Adequate donor management offers an opportunity to reduce organ injury and maximise the number of organs than can be offered in order to respect the donor's altruistic gift. The cornerstones of management include: correction of hypovolaemia; maintenance of organ perfusion; prompt treatment of diabetes insipidus; corticosteroid therapy; and lung protective ventilation. The interventions used to deliver these goals are largely based on pathophysiological rationale or extrapolations from general critical care patients. There is currently insufficient high-quality evidence that has assessed whether any interventions in the donor after brain death may actually improve immediate post-transplant function and long-term graft survival or recipient survival after transplantation. Improvements in our understanding of the underlying mechanisms following brain death, in particular the role of immunological and metabolic changes in donors, offer promising future therapeutic opportunities to increase organ utilisation. Establishing a UK donor management research programme involves consideration of ethical, logistical and legal issues that will benefit transplanted patients while respecting the wishes of donors and their families.
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Affiliation(s)
- K D Bera
- Oxford Biomedical Research Centre and Oxford University Hospital NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - A Shah
- Radcliffe Department of Medicine, University of Oxford, Oxford, UK.,Nuffield Department of Anaesthesia, John Radcliffe Hospital, Oxford, UK
| | - M R English
- University of Oxford Medical School, Oxford, UK
| | - D Harvey
- Department of Intensive Care Medicine, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - R J Ploeg
- Nuffield Department of Surgical Sciences and Oxford Biomedical Research Centre, University of Oxford, UK
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28
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Franzin R, Stasi A, Fiorentino M, Stallone G, Cantaluppi V, Gesualdo L, Castellano G. Inflammaging and Complement System: A Link Between Acute Kidney Injury and Chronic Graft Damage. Front Immunol 2020; 11:734. [PMID: 32457738 PMCID: PMC7221190 DOI: 10.3389/fimmu.2020.00734] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Accepted: 03/31/2020] [Indexed: 12/13/2022] Open
Abstract
The aberrant activation of complement system in several kidney diseases suggests that this pillar of innate immunity has a critical role in the pathophysiology of renal damage of different etiologies. A growing body of experimental evidence indicates that complement activation contributes to the pathogenesis of acute kidney injury (AKI) such as delayed graft function (DGF) in transplant patients. AKI is characterized by the rapid loss of the kidney's excretory function and is a complex syndrome currently lacking a specific medical treatment to arrest or attenuate progression in chronic kidney disease (CKD). Recent evidence suggests that independently from the initial trigger (i.e., sepsis or ischemia/reperfusions injury), an episode of AKI is strongly associated with an increased risk of subsequent CKD. The AKI-to-CKD transition may involve a wide range of mechanisms including scar-forming myofibroblasts generated from different sources, microvascular rarefaction, mitochondrial dysfunction, or cell cycle arrest by the involvement of epigenetic, gene, and protein alterations leading to common final signaling pathways [i.e., transforming growth factor beta (TGF-β), p16 ink4a , Wnt/β-catenin pathway] involved in renal aging. Research in recent years has revealed that several stressors or complications such as rejection after renal transplantation can lead to accelerated renal aging with detrimental effects with the establishment of chronic proinflammatory cellular phenotypes within the kidney. Despite a greater understanding of these mechanisms, the role of complement system in the context of the AKI-to-CKD transition and renal inflammaging is still poorly explored. The purpose of this review is to summarize recent findings describing the role of complement in AKI-to-CKD transition. We will also address how and when complement inhibitors might be used to prevent AKI and CKD progression, therefore improving graft function.
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Affiliation(s)
- Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Vincenzo Cantaluppi
- Department Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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29
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Jager NM, van Zanden JE, Subías M, Leuvenink HGD, Daha MR, Rodríguez de Córdoba S, Poppelaars F, Seelen MA. Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model. Front Immunol 2019; 10:2528. [PMID: 31736957 PMCID: PMC6838866 DOI: 10.3389/fimmu.2019.02528] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 10/11/2019] [Indexed: 12/28/2022] Open
Abstract
Introduction: The majority of kidneys used for transplantation are retrieved from brain-dead organ donors. In brain death, the irreversible loss of brain functions results in hemodynamic instability, hormonal changes and immunological activation. Recently, brain death has been shown to cause activation of the complement system, which is adversely associated with renal allograft outcome in recipients. Modulation of the complement system in the brain-dead donor might be a promising strategy to improve organ quality before transplantation. This study investigated the effect of an inhibitory antibody against complement factor B on brain death-induced renal inflammation and injury. Method: Brain death was induced in male Fischer rats by inflating a balloon catheter in the epidural space. Anti-factor B (anti-FB) or saline was administered intravenously 20 min before the induction of brain death (n = 8/group). Sham-operated rats served as controls (n = 4). After 4 h of brain death, renal function, renal injury, and inflammation were assessed. Results: Pretreatment with anti-FB resulted in significantly less systemic and local complement activation than in saline-treated rats after brain death. Moreover, anti-FB treatment preserved renal function, reflected by significantly reduced serum creatinine levels compared to saline-treated rats after 4 h of brain death. Furthermore, anti-FB significantly attenuated histological injury, as seen by reduced tubular injury scores, lower renal gene expression levels (>75%) and renal deposition of kidney injury marker-1. In addition, anti-FB treatment significantly prevented renal macrophage influx and reduced systemic IL-6 levels compared to saline-treated rats after brain death. Lastly, renal gene expression of IL-6, MCP-1, and VCAM-1 were significantly reduced in rats treated with anti-FB. Conclusion: This study shows that donor pretreatment with anti-FB preserved renal function, reduced renal damage and inflammation prior to transplantation. Therefore, inhibition of factor B in organ donors might be a promising strategy to reduce brain death-induced renal injury and inflammation.
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Affiliation(s)
- Neeltina M Jager
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Judith E van Zanden
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Marta Subías
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.,Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Henri G D Leuvenink
- Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Mohamed R Daha
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.,Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
| | - Santiago Rodríguez de Córdoba
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.,Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
| | - Felix Poppelaars
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Marc A Seelen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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30
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Optimizing organs for transplantation; advancements in perfusion and preservation methods. Transplant Rev (Orlando) 2019; 34:100514. [PMID: 31645271 DOI: 10.1016/j.trre.2019.100514] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/20/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023]
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31
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Grafals M, Thurman JM. The Role of Complement in Organ Transplantation. Front Immunol 2019; 10:2380. [PMID: 31636644 PMCID: PMC6788431 DOI: 10.3389/fimmu.2019.02380] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Accepted: 09/23/2019] [Indexed: 12/17/2022] Open
Abstract
The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical problem. Greater understanding of the immunologic mechanisms that cause allograft failure are needed, as well as new treatment strategies for protecting transplanted organs. The complement cascade is an important part of the innate immune system. Studies have shown that complement activation contributes to allograft injury in several clinical settings, including ischemia/reperfusion injury and antibody mediated rejection. Furthermore, the complement system plays critical roles in modulating the responses of T cells and B cells to antigens. Therapeutic complement inhibitors, therefore, may be effective for protecting transplanted organs from several causes of inflammatory injury. Although several anti-complement drugs have shown promise in selected patients, the role of these drugs in transplantation medicine requires further study.
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Affiliation(s)
- Monica Grafals
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
| | - Joshua M Thurman
- Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States
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32
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Abstract
Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia-reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HLA incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.
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33
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Le Berre L, Danger R, Mai HL, Amon R, Leviatan Ben-Arye S, Bruneau S, Senage T, Perreault H, Teraiya M, Nguyen TVH, Le Tourneau T, Yu H, Chen X, Galli C, Roussel JC, Manez R, Costa C, Brouard S, Galinanes M, Harris KM, Gitelman S, Cozzi E, Charreau B, Padler-Karavani V, Soulillou JP. Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome. Xenotransplantation 2019; 26:e12535. [PMID: 31293002 DOI: 10.1111/xen.12535] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/10/2019] [Accepted: 05/17/2019] [Indexed: 12/12/2022]
Abstract
Humans cannot synthesize N-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet-induced anti-Neu5Gc Abs occurs in all normal individuals, endothelium activation by elicited anti-Neu5Gc Abs following a challenge with animal-derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity-purified anti-Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc-glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre-existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti-Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre-existing or anti-human T-cell globulin (ATG)-elicited anti-Neu5Gc Abs. Compared with pre-existing anti-Neu5Gc Abs, which are normal component of ECs environment, elicited anti-Neu5Gc Abs down-regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement-containing serum down-regulated most transcripts mobilized by serum alone. Both types of anti-Neu5Gc Abs-induced a dose- and complement-dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre-existing anti-Neu5Gc Abs, ATG-elicited anti-Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.
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Affiliation(s)
- Ludmilla Le Berre
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Richard Danger
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Hoa L Mai
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Ron Amon
- Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Shani Leviatan Ben-Arye
- Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Sarah Bruneau
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Thomas Senage
- Service de Chirurgie Cardio-Thoracique, CHU Nantes, Hopital Laennec, Nantes, France
| | - Helene Perreault
- Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Milan Teraiya
- Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Thi Van Ha Nguyen
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | | | - Hai Yu
- Department of Chemistry, University of California-Davis, Davis, California
| | - Xi Chen
- Department of Chemistry, University of California-Davis, Davis, California
| | - Cesare Galli
- Avantea, Laboratory of Reproductive Technologies and Fondazione Avantea, Cremona, Italy
| | | | - Rafael Manez
- Intensive Care Medicine Department, Hospital Universitario de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.,Infectious Diseases and Transplantation Division, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Cristina Costa
- Infectious Diseases and Transplantation Division, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Sophie Brouard
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Manuel Galinanes
- Department of Cardiac Surgery/Reparative Therapy of the Heart, Vall d'Hebron Research Institute and University Hospital Vall d'Hebron, Barcelona, Spain
| | - Kristina M Harris
- Immune Tolerance Network, Massachusetts General Hospital, Bathesda, Maryland
| | - Stephen Gitelman
- Division of Pediatric Endocrinology and Diabetes, University of California at San Francisco, San Francisco, California
| | - Emanuele Cozzi
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Beatrice Charreau
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
| | - Vered Padler-Karavani
- Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Jean-Paul Soulillou
- Centre de Recherche en Transplantation et Immunologie (CRTI), INSERM, Université de Nantes, Nantes, France.,Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
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34
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van Zanden JE, Jager NM, Daha MR, Erasmus ME, Leuvenink HGD, Seelen MA. Complement Therapeutics in the Multi-Organ Donor: Do or Don't? Front Immunol 2019; 10:329. [PMID: 30873176 PMCID: PMC6400964 DOI: 10.3389/fimmu.2019.00329] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 02/08/2019] [Indexed: 12/18/2022] Open
Abstract
Over the last decade, striking progress has been made in the field of organ transplantation, such as better surgical expertise and preservation techniques. Therefore, organ transplantation is nowadays considered a successful treatment in end-stage diseases of various organs, e.g. the kidney, liver, intestine, heart, and lungs. However, there are still barriers which prevent a lifelong survival of the donor graft in the recipient. Activation of the immune system is an important limiting factor in the transplantation process. As part of this pro-inflammatory environment, the complement system is triggered. Complement activation plays a key role in the transplantation process, as highlighted by the amount of studies in ischemia-reperfusion injury (IRI) and rejection. However, new insight have shown that complement is not only activated in the later stages of transplantation, but already commences in the donor. In deceased donors, complement activation is associated with deteriorated quality of deceased donor organs. Of importance, since most donor organs are derived from either brain-dead donors or deceased after circulatory death donors. The exact mechanisms and the role of the complement system in the pathophysiology of the deceased donor have been underexposed. This review provides an overview of the current knowledge on complement activation in the (multi-)organ donor. Targeting the complement system might be a promising therapeutic strategy to improve the quality of various donor organs. Therefore, we will discuss the complement therapeutics that already have been tested in the donor. Finally, we question whether complement therapeutics should be translated to the clinics and if all organs share the same potential complement targets, considering the physiological differences of each organ.
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Affiliation(s)
- Judith E. van Zanden
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Neeltina M. Jager
- Department of Surgery, University Medical Center Groningen, Groningen, Netherlands
| | - Mohamed R. Daha
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
| | - Michiel E. Erasmus
- Department of Thoracic Surgery, University Medical Center Groningen, Groningen, Netherlands
| | | | - Marc A. Seelen
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, Groningen, Netherlands
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35
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Nieuwenhuijs-Moeke GJ, Nieuwenhuijs VB, Seelen MAJ, Berger SP, van den Heuvel MC, Burgerhof JGM, Ottens PJ, Ploeg RJ, Leuvenink HGD, Struys MMRF. Propofol-based anaesthesia versus sevoflurane-based anaesthesia for living donor kidney transplantation: results of the VAPOR-1 randomized controlled trial. Br J Anaesth 2018; 118:720-732. [PMID: 28510740 DOI: 10.1093/bja/aex057] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2017] [Indexed: 12/22/2022] Open
Abstract
Background Kidney transplantation is associated with harmful processes affecting the viability of the graft. One of these processes is associated with the phenomenon of ischaemia-reperfusion injury. Anaesthetic conditioning is a widely described strategy to attenuate ischaemia-reperfusion injury. We therefore conducted the Volatile Anaesthetic Protection of Renal Transplants-1 trial, a pilot project evaluating the influence of two anaesthetic regimens, propofol- vs sevoflurane-based anaesthesia, on biochemical and clinical outcomes in living donor kidney transplantation. Methods Sixty couples were randomly assigned to the following three groups: PROP (donor and recipient propofol), SEVO (donor and recipient sevoflurane), and PROSE (donor propofol and recipient sevoflurane). The primary outcome was renal injury reflected by urinary biomarkers. The follow-up period was 2 yr. Results Three couples were excluded, leaving 57 couples for analysis. Concentrations of kidney injury molecule-1 (KIM-1), N -acetyl-β- d -glucosaminidase (NAG), and heart-type fatty acid binding protein (H-FABP) in the first urine upon reperfusion showed no differences. On day 2, KIM-1 concentrations were higher in SEVO [952.8 (interquartile range 311.8-1893.0) pg mmol -1 ] compared with PROP [301.2 (202.0-504.7) pg mmol -1 ]. This was the same for NAG: SEVO, 1.835 (1.162-2.457) IU mmol -1 vs PROP, 1.078 (0.819-1.713) IU mmol -1 . Concentrations of H-FABP showed no differences. Measured glomerular filtration rate at 3, 6, and 12 months showed no difference. After 2 yr, there was a difference in the acute rejection rate ( P =0.039). Post hoc testing revealed a difference between PROP (35%) and PROSE (5%; P =0.020). The difference between PROP and SEVO (11%) was not significant ( P =0.110). Conclusions The SEVO group showed higher urinary KIM-1 and NAG concentrations in living donor kidney transplantation on the second day after transplantation. This was not reflected in inferior graft outcome. Clinical trial registration NCT01248871.
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Affiliation(s)
| | - V B Nieuwenhuijs
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.,Department of Surgery, Isala, Zwolle, The Netherlands
| | | | | | | | - J G M Burgerhof
- Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - P J Ottens
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - R J Ploeg
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.,Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
| | - H G D Leuvenink
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - M M R F Struys
- Department of Anaesthesiology.,Department of Anaesthesia, Ghent University, Ghent, Belgium
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36
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Cheng Q, Patel K, Lei B, Rucker L, Allen DP, Zhu P, Vasu C, Martins PN, Goddard M, Nadig SN, Atkinson C. Donor pretreatment with nebulized complement C3a receptor antagonist mitigates brain-death induced immunological injury post-lung transplant. Am J Transplant 2018; 18:2417-2428. [PMID: 29504277 PMCID: PMC6123303 DOI: 10.1111/ajt.14717] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 02/16/2018] [Accepted: 02/19/2018] [Indexed: 01/25/2023]
Abstract
Donor brain death (BD) is an inherent part of lung transplantation (LTx) and a key contributor to ischemia-reperfusion injury (IRI). Complement activation occurs as a consequence of BD in other solid organ Tx and exacerbates IRI, but the role of complement in LTx has not been investigated. Here, we investigate the utility of delivering nebulized C3a receptor antagonist (C3aRA) pretransplant to BD donor lungs in order to reduce post-LTx IRI. BD was induced in Balb/c donors, and lungs nebulized with C3aRA or vehicle 30 minutes prior to lung procurement. Lungs were then cold stored for 18 hours before transplantation into C57Bl/6 recipients. Donor lungs from living donors (LD) were removed and similarly stored. At 6 hours and 5 days post-LTx, recipients of BD donor lungs had exacerbated IRI and acute rejection (AR), respectively, compared to recipients receiving LD lungs, as determined by increased histopathological injury, immune cells, and cytokine levels. A single pretransplant nebulized dose of C3aRA to the donor significantly reduced IRI as compared to vehicle-treated BD donors, and returned IRI and AR grades to that seen following LD LTx. These data demonstrate a role for complement inhibition in the amelioration of IRI post-LTx in the context of donor BD.
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Affiliation(s)
- Qi Cheng
- Institute of Organ Transplantation, Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,430030, China,Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA,Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Kunal Patel
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA,Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Biao Lei
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
| | - Lindsay Rucker
- Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - D. Patterson Allen
- Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Peng Zhu
- Institute of Organ Transplantation, Department of Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan,430030, China,Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA,Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Chentha Vasu
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
| | - Paulo N. Martins
- University of Massachusetts, UMass Memorial Medical Center, Department of Surgery, Transplant Division, Worcester, MA 01655, USA
| | - Martin Goddard
- Pathology Department, Papworth Hospital NHS Trust, Papworth Everard, Cambridge, England, CB3 8RE
| | - Satish N. Nadig
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA,Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA,South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA
| | - Carl Atkinson
- Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA,Department of Surgery, Division of Transplant, Lee Patterson Allen Transplant Immunobiology Laboratory, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA,South Carolina Investigators in Transplantation (SCIT), Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA,Address for Correspondence. Dr Carl Atkinson, PhD. Department of Microbiology and Immunology, and Surgery. Medical University of South Carolina, Lee Patterson Allen Transplant Immunobiology Laboratory, Basic Science Department, 173 Ashley Avenue, Charleston, SC 29425 USA. Tel: 1-843-792-1716. Fax: 1-843-792-2464.
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Abstract
BACKGROUND Kidneys derived from brain-dead (BD) donors have lower graft survival rates compared with kidneys from living donors. Complement activation plays an important role in brain death. The aim of our study was therefore to investigate the effect of C1-inhibitor (C1-INH) on BD-induced renal injury. METHODS Brain death was induced in rats by inflating a subdurally placed balloon catheter. Thirty minutes after BD, rats were treated with saline, low-dose or high-dose C1-INH. Sham-operated rats served as controls. After 4 hours of brain death, renal function, injury, inflammation, and complement activation were assessed. RESULTS High-dose C1-INH treatment of BD donors resulted in significantly lower renal gene expression and serum levels of IL-6. Treatment with C1-INH also improved renal function and reduced renal injury, reflected by the significantly lower kidney injury marker 1 gene expression and lower serum levels of lactate dehydrogenase and creatinine. Furthermore, C1-INH effectively reduced complement activation by brain death and significantly increased functional levels. However, C1-INH treatment did not prevent renal cellular influx. CONCLUSIONS Targeting complement activation after the induction of brain death reduced renal inflammation and improved renal function before transplantation. Therefore, strategies targeting complement activation in human BD donors might clinically improve donor organ viability and renal allograft survival.
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Bartoszek D, Mazanowska O, Kościelska-Kasprzak K, Kamińska D, Lepiesza A, Chudoba P, Myszka M, Żabińska M, Klinger M. Functional Activity of the Complement System in Deceased Donors in Relation to Kidney Allograft Outcome. Transplant Proc 2018; 50:1697-1700. [PMID: 30056884 DOI: 10.1016/j.transproceed.2018.02.157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 02/06/2018] [Indexed: 11/28/2022]
Abstract
Complement activation is considered one of the mediators of renal ischemia-reperfusion injury. Elevated levels of C5b-9, C3a, and C5a are detected in sera of deceased kidney donors. The goal of the study was to characterize the functional activity of complement pathways in donor sera and to assess their influence on transplant outcome. MATERIALS AND METHODS Sixty-four deceased kidney donors (age 45 ± 16 years; 28 female, 36 male) and 27 healthy controls (age 42 ± 12 years; 14 female, 13 male) were enrolled in the study. The results of transplantation for the respective 122 kidney recipients were included in the analysis. The functional activities of classical (CP), lectin (LP), and alternative (AP) pathways were measured using Wielisa-kit (reference normal level = 100%). In most cases, decreased functional activity reflects the activation status of the pathway. RESULTS The median (interquartile range) functional activities of the pathways in donor sera were CP 118 (89-150)%, LP 80 (20-127)%, and AP 74 (50-89)%, and did not differ from the control values CP 110 (102-115)%, LP 81 (26-106)%, AP 76 (61-88)%. The frequency of pathway activation observed in controls was CP 0%, LP 11%, and AP 0%. Deceased donors did not differ in activation of classical (11%) and lectin (13%) pathways, but presented a higher rate of alternative pathway activation (19%, P = .03). No significant influence of any pathway functional activity or its activation was proved to influence the transplant outcome. CONCLUSION Complement activation via alternative pathway was observed in diseased donor sera. No predictive potential of donor complement functional activity on the transplant outcome could be proved.
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Affiliation(s)
- D Bartoszek
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - O Mazanowska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.
| | - K Kościelska-Kasprzak
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - D Kamińska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - A Lepiesza
- Department of Vascular, General, and Transplant Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - P Chudoba
- Department of Vascular, General, and Transplant Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - M Myszka
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - M Żabińska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
| | - M Klinger
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland
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39
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Román E, Mendizábal S, Jarque I, de la Rubia J, Sempere A, Morales E, Praga M, Ávila A, Górriz JL. Secondary thrombotic microangiopathy and eculizumab: A reasonable therapeutic option. Nefrologia 2018; 37:478-491. [PMID: 28946961 DOI: 10.1016/j.nefro.2017.01.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 01/03/2017] [Accepted: 01/14/2017] [Indexed: 12/16/2022] Open
Abstract
Understanding the role of the complement system in the pathogenesis of atypical haemolytic uraemic syndrome and other thrombotic microangiopathies (TMA) has led to the use of anti-complement therapy with eculizumab in these diseases, in addition to its original use in patients with paroxysmal nocturnal haemoglobinuria andatypical haemolytic uraemic syndrome. Scientific evidence shows that both primary and secondary TMAs with underlying complement activation are closely related. For this reasons, control over the complement system is a therapeutic target. There are 2scenarios in which eculizumab is used in patients with TMA: primary or secondary TMA that is difficult to differentiate (including incomplete clinical presentations) and complement-mediated damage in various processes in which eculizumab proves to be efficacious. This review summarises the evidence on the role of the complement activation in the pathophysiology of secondary TMAs and the efficacy of anti-complement therapy in TMAs secondary to pregnancy, drugs, transplant, humoral rejection, systemic diseases and glomerulonephritis. Although experience is scarce, a good response to eculizumab has been reported in patients with severe secondary TMAs refractory to conventional treatment. Thus, the role of the anti-complement therapy as a new treatment option in these patients should be investigated.
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Affiliation(s)
- Elena Román
- Servicio de Nefrología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, España.
| | - Santiago Mendizábal
- Servicio de Nefrología Pediátrica, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Isidro Jarque
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Javier de la Rubia
- Servicio de Hematología, Hospital Universitario Dr. Peset, Valencia, España
| | - Amparo Sempere
- Servicio de Hematología, Hospital Universitario y Politécnico La Fe, Valencia, España
| | - Enrique Morales
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Manuel Praga
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, España
| | - Ana Ávila
- Servicio de Nefrología, Hospital Universitario Dr. Peset, Valencia, España
| | - José Luis Górriz
- Servicio de Nefrología, Hospital Universitario Dr. Peset, Valencia, España
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40
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Núñez K, Thevenot P, Alfadhli A, Cohen A. Complement Activation in Liver Transplantation: Role of Donor Macrosteatosis and Implications in Delayed Graft Function. Int J Mol Sci 2018; 19:1750. [PMID: 29899265 PMCID: PMC6032339 DOI: 10.3390/ijms19061750] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 05/28/2018] [Accepted: 06/08/2018] [Indexed: 12/16/2022] Open
Abstract
The complement system anchors the innate inflammatory response by triggering both cell-mediated and antibody-mediated immune responses against pathogens. The complement system also plays a critical role in sterile tissue injury by responding to damage-associated molecular patterns. The degree and duration of complement activation may be a critical variable controlling the balance between regenerative and destructive inflammation following sterile injury. Recent studies in kidney transplantation suggest that aberrant complement activation may play a significant role in delayed graft function following transplantation, confirming results obtained from rodent models of renal ischemia/reperfusion (I/R) injury. Deactivating the complement cascade through targeting anaphylatoxins (C3a/C5a) might be an effective clinical strategy to dampen reperfusion injury and reduce delayed graft function in liver transplantation. Targeting the complement cascade may be critical in donor livers with mild to moderate steatosis, where elevated lipid burden amplifies stress responses and increases hepatocyte turnover. Steatosis-driven complement activation in the donor liver may also have implications in rejection and thrombolytic complications following transplantation. This review focuses on the roles of complement activation in liver I/R injury, strategies to target complement activation in liver I/R, and potential opportunities to translate these strategies to transplanting donor livers with mild to moderate steatosis.
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Affiliation(s)
- Kelley Núñez
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
| | - Abeer Alfadhli
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
| | - Ari Cohen
- Institute of Translational Research, Ochsner Health System, New Orleans, LA 70121, USA.
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41
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Yang J, Snijders MLH, Haasnoot GW, van Kooten C, Mallat M, de Fijter JW, Clahsen-van Groningen MC, Claas FHJ, Eikmans M. Elevated intragraft expression of innate immunity and cell death-related markers is a risk factor for adverse graft outcome. Transpl Immunol 2018; 48:39-46. [PMID: 29475090 DOI: 10.1016/j.trim.2018.02.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 02/13/2018] [Accepted: 02/14/2018] [Indexed: 12/26/2022]
Abstract
BACKGROUND Molecules of the innate immune response are increasingly recognized as important mediators in allograft injury during and after kidney transplantation. We therefore aimed to establish the relationship between the expression of these genes at implantation, during an acute rejection (AR) and on graft outcome. METHODS A total of 19 genes, including Toll like receptors (TLRs), complement components and regulators, and apoptosis-related genes were analyzed at the mRNA level by qPCR in 123 biopsies with acute rejection and paired pre-transplantation tissue (n = 75). RESULTS Before transplantation, relative mRNA expression of BAX:BCL2 ratio (apoptosis marker) and several complement genes was significantly higher in tissue samples from deceased donors compared to living donors. During AR, TLRs and complement genes showed an increased expression compared to pre-transplant conditions, whereas complement regulators were decreased. A relatively high TLR4 expression level and BAX:BCL2 ratio during AR in the deceased donor group was associated with adverse graft outcome, independently of clinical risk factors. CONCLUSIONS Complement- and apoptosis-related gene expression is elevated in deceased donor transplants before transplantation. High BAX:BCL2 ratio and TLR4 expression during AR may reflect enhanced intragraft cell death and immunogenic danger signals, and pose a risk factor for adverse graft outcome.
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Affiliation(s)
- Jianxin Yang
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Geert W Haasnoot
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Cees van Kooten
- Dept. of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marko Mallat
- Dept. of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Johan W de Fijter
- Dept. of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Frans H J Claas
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Michael Eikmans
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
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42
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Loeschenberger B, Niess L, Würzner R, Schwelberger H, Eder IE, Puhr M, Guenther J, Troppmair J, Rudnicki M, Neuwirt H. Calcineurin inhibitor-induced complement system activation via ERK1/2 signalling is inhibited by SOCS-3 in human renal tubule cells. Eur J Immunol 2017; 48:330-343. [PMID: 29143318 DOI: 10.1002/eji.201747135] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 09/12/2017] [Accepted: 11/03/2017] [Indexed: 12/22/2022]
Abstract
One factor that significantly contributes to renal allograft loss is chronic calcineurin inhibitor (CNI) nephrotoxicity (CIN). Among other factors, the complement (C-) system has been proposed to be involved CIN development. Hence, we investigated the impact of CNIs on intracellular signalling and the effects on the C-system in human renal tubule cells. In a qPCR array, CNI treatment upregulated C-factors and downregulated SOCS-3 and the complement inhibitors CD46 and CD55. Additionally, ERK1/-2 was required for these regulations. Following knock-down and overexpression of SOCS-3, we found that SOCS-3 inhibits ERK1/-2 signalling. Finally, we assessed terminal complement complex formation, cell viability and apoptosis. Terminal complement complex formation was induced by CNIs. Cell viability was significantly decreased, whereas apoptosis was increased. Both effects were reversed under complement component-depleted conditions. In vivo, increased ERK1/-2 phosphorylation and SOCS-3 downregulation were observed at the time of transplantation in renal allograft patients who developed a progressive decline of renal function in the follow-up compared to stable patients. The progressive cohort also had lower total C3 levels, suggesting higher complement activity at baseline. In conclusion, our data suggest that SOCS-3 inhibits CNI-induced ERK1/-2 signalling, thereby blunting the negative control of C-system activation.
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Affiliation(s)
| | - Lea Niess
- Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
| | - Reinhard Würzner
- Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria
| | - Hubert Schwelberger
- Molecular Biology Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Iris E Eder
- Department of Urology, Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria
| | - Martin Puhr
- Department of Urology, Division of Experimental Urology, Innsbruck Medical University, Innsbruck, Austria
| | - Julia Guenther
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Jakob Troppmair
- Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University, Innsbruck, Austria
| | - Michael Rudnicki
- Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
| | - Hannes Neuwirt
- Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria
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43
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Cernoch M, Viklicky O. Complement in Kidney Transplantation. Front Med (Lausanne) 2017; 4:66. [PMID: 28611987 PMCID: PMC5447724 DOI: 10.3389/fmed.2017.00066] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 05/09/2017] [Indexed: 12/12/2022] Open
Abstract
The complement system is considered to be an important part of innate immune system with a significant role in inflammation processes. The activation can occur through classical, alternative, or lectin pathway, resulting in the creation of anaphylatoxins C3a and C5a, possessing a vast spectrum of immune functions, and the assembly of terminal complement cascade, capable of direct cell lysis. The activation processes are tightly regulated; inappropriate activation of the complement cascade plays a significant role in many renal diseases including organ transplantation. Moreover, complement cascade is activated during ischemia/reperfusion injury processes and influences delayed graft function of kidney allografts. Interestingly, complement system has been found to play a role in both acute cellular and antibody-mediated rejections and thrombotic microangiopathy. Therefore, complement system may represent an interesting therapeutical target in kidney transplant pathologies.
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Affiliation(s)
- Marek Cernoch
- Transplant Laboratory, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia
| | - Ondrej Viklicky
- Transplant Laboratory, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia.,Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia
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44
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Jager NM, Poppelaars F, Daha MR, Seelen MA. Complement in renal transplantation: The road to translation. Mol Immunol 2017; 89:22-35. [PMID: 28558950 DOI: 10.1016/j.molimm.2017.05.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 05/17/2017] [Accepted: 05/19/2017] [Indexed: 02/08/2023]
Abstract
Renal transplantation is the treatment of choice for patients with end-stage renal disease. The vital role of the complement system in renal transplantation is widely recognized. This review discusses the role of complement in the different phases of renal transplantation: in the donor, during preservation, in reperfusion and at the time of rejection. Here we examine the current literature to determine the importance of both local and systemic complement production and how complement activation contributes to the pathogenesis of renal transplant injury. In addition, we dissect the complement pathways involved in the different phases of renal transplantation. We also review the therapeutic strategies that have been tested to inhibit complement during the kidney transplantation. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition for the treatment of brain death-induced renal injury, renal ischemia-reperfusion injury and acute rejection. We conclude that it is expected that in the near future, complement-targeted therapeutics will be used clinically in renal transplantation. This will hopefully result in improved renal graft function and increased graft survival.
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Affiliation(s)
- Neeltina M Jager
- Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Felix Poppelaars
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Mohamed R Daha
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Nephrology, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands
| | - Marc A Seelen
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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45
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Zwang NA, Leventhal JR. Cell Therapy in Kidney Transplantation: Focus on Regulatory T Cells. J Am Soc Nephrol 2017; 28:1960-1972. [PMID: 28465379 DOI: 10.1681/asn.2016111206] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Renal transplantation is the renal replacement modality of choice for suitable candidates with advanced CKD or ESRD. Prevention of rejection, however, requires treatment with nonspecific pharmacologic immunosuppressants that carry both systemic and nephrologic toxicities. Use of a patient's own suppressive regulatory T cells (Tregs) is an attractive biologic approach to reduce this burden. Here, we review the immunologic underpinnings of Treg therapy and technical challenges to developing successful cell therapy. These issues include the selection of appropriate Treg subsets, ex vivo Treg expansion approaches, how many Tregs to administer and when, and how to care for patients after Treg administration.
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Affiliation(s)
| | - Joseph R Leventhal
- Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, Illinois
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46
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Poppelaars F, van Werkhoven MB, Kotimaa J, Veldhuis ZJ, Ausema A, Broeren SGM, Damman J, Hempel JC, Leuvenink HGD, Daha MR, van Son WJ, van Kooten C, van Os RP, Hillebrands JL, Seelen MA. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury. FASEB J 2017; 31:3193-3204. [PMID: 28396344 DOI: 10.1096/fj.201601218r] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 03/27/2017] [Indexed: 01/15/2023]
Abstract
The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR injury; however, the role of C5aR2 in IR injury is less clear as initial studies proposed the hypothesis that C5aR2 functions as a decoy receptor. By Using wild-type, C5aR1-/-, and C5aR2-/- mice in a model of renal IR injury, we found that a deficiency of either of these receptors protected mice from renal IR injury. Surprisingly, C5aR2-/- mice were most protected and had lower creatinine levels and reduced acute tubular necrosis. Next, an in vivo migration study demonstrated that leukocyte chemotaxis was unaffected in C5aR2-/- mice, whereas neutrophil activation was reduced by C5aR2 deficiency. To further investigate the contribution of renal cell-expressed C5aR2 vs leukocyte-expressed C5aR2 to renal IR injury, bone marrow chimeras were created. Our data show that both renal cell-expressed C5aR2 and leukocyte-expressed C5aR2 mediate IR-induced renal dysfunction. These studies reveal the importance of C5aR2 in renal IR injury. They further show that C5aR2 is a functional receptor, rather than a decoy receptor, and may provide a new target for intervention.-Poppelaars, F., van Werkhoven, M. B., Kotimaa, J., Veldhuis, Z. J., Ausema, A., Broeren, S. G. M., Damman, J., Hempel, J. C., Leuvenink, H. G. D., Daha, M. R., van Son, W. J., van Kooten, C., van Os, R. P., Hillebrands, J.-L., Seelen, M. A. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury.
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Affiliation(s)
- Felix Poppelaars
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Maaike B van Werkhoven
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Juha Kotimaa
- Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Zwanida J Veldhuis
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Albertina Ausema
- Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stefan G M Broeren
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Jeffrey Damman
- Department of Pathology, University of Amsterdam, Academic Medical Centre, Amsterdam, The Netherlands
| | - Julia C Hempel
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Henri G D Leuvenink
- Department of Surgery, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Mohamed R Daha
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.,Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Willem J van Son
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Cees van Kooten
- Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Ronald P van Os
- Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Jan-Luuk Hillebrands
- Division of Pathology, Department of Pathology and Medical Biology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Marc A Seelen
- Division of Nephrology, Department of Internal Medicine, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands;
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47
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Salvadori M, Tsalouchos A. Pre-transplant biomarkers and prediction of post-transplant outcomes in kidney transplantation. J Renal Inj Prev 2017; 6:222-230. [DOI: 10.15171/jrip.2017.42] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
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48
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Poppelaars F, Seelen MA. Complement-mediated inflammation and injury in brain dead organ donors. Mol Immunol 2016; 84:77-83. [PMID: 27989433 DOI: 10.1016/j.molimm.2016.11.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 11/08/2016] [Accepted: 11/08/2016] [Indexed: 01/16/2023]
Abstract
The importance of the complement system in renal ischemia-reperfusion injury and acute rejection is widely recognized, however its contribution to the pathogenesis of tissue damage in the donor remains underexposed. Brain-dead (BD) organ donors are still the primary source of organs for transplantation. Brain death is characterized by hemodynamic changes, hormonal dysregulation, and immunological activation. Recently, the complement system has been shown to be involved. In BD organ donors, complement is activated systemically and locally and is an important mediator of inflammation and graft injury. Furthermore, complement activation can be used as a clinical marker for the prediction of graft function after transplantation. Experimental models of BD have shown that inhibition of the complement cascade is a successful method to reduce inflammation and injury of donor grafts, thereby improving graft function and survival after transplantation. Consequently, complement-targeted therapeutics in BD organ donors form a new opportunity to improve organ quality for transplantation. Future studies should further elucidate the mechanism responsible for complement activation in BD organ donors.
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Affiliation(s)
- Felix Poppelaars
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands
| | - Marc A Seelen
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.
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Zheng QY, Liang SJ, Li GQ, Lv YB, Li Y, Tang M, Zhang K, Xu GL, Zhang KQ. Complement component 3 deficiency prolongs MHC-II disparate skin allograft survival by increasing the CD4(+) CD25(+) regulatory T cells population. Sci Rep 2016; 6:33489. [PMID: 27641978 PMCID: PMC5027598 DOI: 10.1038/srep33489] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022] Open
Abstract
Recent reports suggest that complement system contributes to allograft rejection. However, its underlying mechanism is poorly understood. Herein, we investigate the role of complement component 3 (C3) in a single MHC-II molecule mismatched murine model of allograft rejection using C3 deficient mice (C3−/−) as skin graft donors or recipients. Compared with C3+/+ B6 allografts, C3−/− B6 grafts dramatically prolonged survival in MHC-II molecule mismatched H-2bm12 B6 recipients, indicating that C3 plays a critical role in allograft rejection. Compared with C3+/+ allografts, both Th17 cell infiltration and Th1/Th17 associated cytokine mRNA levels were clearly reduced in C3−/− allografts. Moreover, C3−/− allografts caused attenuated Th1/Th17 responses, but increased CD4+CD25+Foxp3+ regulatory T (Treg) cell expression markedly in local intragraft and H-2bm12 recipients. Depletion of Treg cells by anti-CD25 monoclonal antibody (mAb) negated the survival advantages conferred by C3 deficiency. Our results indicate for the first time that C3 deficiency can prolong MHC-II molecule mismatched skin allograft survival, which is further confirmed to be associated with increased CD4+ CD25+ Treg cell population expansion and attenuated Th1/Th17 response.
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Affiliation(s)
- Quan-You Zheng
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.,Department of Urology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Shen-Ju Liang
- Department of Rheumatism and Immunology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Gui-Qing Li
- Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Yan-Bo Lv
- Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - You Li
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ming Tang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Kun Zhang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Gui-Lian Xu
- Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Ke-Qin Zhang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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50
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Schrödl W, Büchler R, Wendler S, Reinhold P, Muckova P, Reindl J, Rhode H. Acute phase proteins as promising biomarkers: Perspectives and limitations for human and veterinary medicine. Proteomics Clin Appl 2016; 10:1077-1092. [PMID: 27274000 DOI: 10.1002/prca.201600028] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/09/2016] [Accepted: 06/01/2016] [Indexed: 12/23/2022]
Abstract
Acute phase proteins (APPs) are highly conserved plasma proteins that are increasingly secreted by the liver in response to a variety of injuries, independently of their location and cause. APPs favor the systemic regulation of defense, coagulation, proteolysis, and tissue repair. Various APPs have been applied as general diagnostic parameters for a long time. Through proteomic techniques, more and more APPs have been discovered to be differentially altered. Since they are not consistently explainable by a stereotypic hepatic expression of sets of APPs, most of these results have unfortunately been neglected or attributed to the nonspecificity of the acute phase reaction. Moreover, it appears that various extrahepatic tissues are also able to express APPs. These extrahepatic APPs show focally specific roles in tissue homeostasis and repair and are released primarily into interstitial and distal fluids. Since these focal proteins might leak into the circulatory system, mixtures of hepatic and extrahepatic APP species can be expected in blood. Hence, a selective alteration of parts of APPs might be expected. There are several hints on multiple molecular forms and fragments of tissue-derived APPs. These differences offer the chance for multiple selective determinations. Thus, specific proteoforms might indeed serve as tissue-specific disease indicators.
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Affiliation(s)
- Wieland Schrödl
- Institute of Bacteriology and Mycology, Veterinary Faculty, University Leipzig, Germany
| | - Rita Büchler
- Institute of Biochemistry I, University Hospital Jena, Germany
| | - Sindy Wendler
- Institute of Biochemistry I, University Hospital Jena, Germany
| | - Petra Reinhold
- Institute of Molecular Pathogenesis at 'Friedrich Loeffler Institut', Federal Research Institute for Animal Health, Jena, Germany
| | - Petra Muckova
- Institute of Biochemistry I, University Hospital Jena, Germany.,Clinic of Neurology, University Hospital Jena, Germany
| | - Johanna Reindl
- Institute of Biochemistry I, University Hospital Jena, Germany
| | - Heidrun Rhode
- Institute of Biochemistry I, University Hospital Jena, Germany
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