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Buxeda A, Crespo M, Chamoun B, Gimeno J, Torres IB, Redondo-Pachón D, Riera M, Burballa C, Pascual J, Mengel M, Adam BA, Pérez-Sáez MJ. Clinical and molecular spectrum of v-lesion. Am J Transplant 2024; 24:2007-2021. [PMID: 39084462 DOI: 10.1016/j.ajt.2024.07.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 07/10/2024] [Accepted: 07/23/2024] [Indexed: 08/02/2024]
Abstract
Isolated v-lesion presents diagnostic stratification and clinical challenges. We characterized allograft outcomes for this entity based on posttransplant time (early: ≤1 month vs late: >1 month) and compared its molecular phenotype with other v+ rejection forms. Using the NanoString B-HOT panel, we analyzed 92 archival formalin-fixed paraffin-embedded tissue kidney biopsies from 3 centers: isolated v-lesion (n = 23), antibody-mediated rejection (ABMR) v+ (n = 26), T cell-mediated rejection (TCMR) v+ (n = 10), mixed rejection v+ (n = 23), and normal tissue (n = 10). Six gene sets (ABMR, DSAST, ENDAT, TCMR, early/acute injury, late injury) were assessed. Early isolated v-lesions had the poorest 1-year death-censored graft survival compared with late isolated v-lesions or other rejections (P = .034). Gene set analysis showed lower TCMR-related gene expression in isolated v+ groups than TCMR and mixed rejection (P < .001). Both early- and late isolated v-lesions had lower ABMR-related gene expression than ABMR, mixed rejection, and TCMR (P ≤ .022). Late isolated v-lesions showed reduced DSAST and ENDAT gene expression versus ABMR (P ≤ .046) and decreased early/acute injury gene expression than early isolated v+, ABMR, TCMR, and mixed rejection (P ≤ .026). In conclusion, isolated v-lesions exhibit distinct gene expression patterns versus other rejection v+ forms. Early isolated v+ is associated with poorer prognosis and increased early/acute injury gene expression than late isolated v+, suggesting distinct etiologies.
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Affiliation(s)
- Anna Buxeda
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.
| | - Marta Crespo
- Department of Nephrology, Hospital del Mar, Barcelona, Spain.
| | - Betty Chamoun
- Department of Nephrology, Hospital del Mar, Barcelona, Spain; Department of Nephrology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Javier Gimeno
- Department of Pathology, Hospital del Mar, Barcelona, Spain
| | - Irina B Torres
- Department of Nephrology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | | | - Marta Riera
- Department of Nephrology, Hospital del Mar Medical Research Institute, Barcelona, Spain
| | - Carla Burballa
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
| | - Benjamin A Adam
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada
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Milesi J, Gras D, Chanez P, Coiffard B. Airway epithelium in lung transplantation: a potential actor for post-transplant complications? Eur Respir Rev 2024; 33:240093. [PMID: 39603662 PMCID: PMC11600126 DOI: 10.1183/16000617.0093-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 09/20/2024] [Indexed: 11/29/2024] Open
Abstract
Lung transplantation, a critical intervention for end-stage lung diseases, is frequently challenged by post-transplant complications. Indeed, primary graft dysfunction, anastomotic complications, infections and acute and chronic rejections pose significant hurdles in lung transplantation. While evidence regarding the role of airway epithelium after lung transplantation is still emerging, its importance is becoming increasingly recognised. This review looks at the complex involvement of airway epithelium in various post-transplant complications, while emphasising the utility of airway epithelial culture as a research model. In summary, by elucidating the involvement of airway epithelium in each post-transplant complication and explaining these intricate processes, the review aims to guide specific future research efforts and therapeutic strategies aimed at improving lung transplant outcomes and enhancing patient care.
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Affiliation(s)
- Jules Milesi
- Aix-Marseille University, APHM, Department of Respiratory Medicine and Lung Transplantation, Marseille, France
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| | - Delphine Gras
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| | - Pascal Chanez
- Aix-Marseille University, APHM, Department of Respiratory Medicine and Lung Transplantation, Marseille, France
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
| | - Benjamin Coiffard
- Aix-Marseille University, APHM, Department of Respiratory Medicine and Lung Transplantation, Marseille, France
- Aix-Marseille University, INSERM, INRAE, C2VN, Marseille, France
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3
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Verdiales C, Baxter L, Lim HJ, Beck G, Moser MA. Matched pair analysis of the effect of longer hypothermic machine perfusion time on kidney transplant outcomes. World J Transplant 2024; 14:95233. [PMID: 39295972 PMCID: PMC11317862 DOI: 10.5500/wjt.v14.i3.95233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/31/2024] [Accepted: 06/26/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Hypothermic machine perfusion (HMP) has demonstrated benefits in terms of early kidney transplant function compared to static cold storage. While longer preservation times have shown detrimental effects, a previous paired study indicated that longer pump times (the second kidney in a pair) might lead to improved outcomes. AIM To revisit the prior paired study's somewhat unexpected results by reviewing our program's experience. METHODS A total of 61 pairs of transplant recipients who received kidneys from the same donor (2012-2021) were analyzed. Patients were divided into two groups depending on whether they were transplanted first (K1) or second (K2). Therefore, the patients in each pair had identical donor characteristics, except for time on the pump. Statistical analyses included Kaplan-Meyer analysis and paired tests, including McNemar's test, student's paired t-test, or Wilcoxon's test, as appropriate. RESULTS The two groups of recipients had similar demographics (age, body mass index, diabetes, time on dialysis, sensitization and retransplants). Cold ischemic times for K1 and K2 were 8.9 (95%CI: 7.9, 9.8) and 14.7 hours (13.7, 15.8) (P < 0.0001), respectively. Overall, K2 had a higher rate of freedom from biopsy-proven acute rejection at 1 year (P = 0.015). Delayed graft function was less common in K2, 12/61 (20%) than in K1, 20/61 (33%) (P = 0.046). Finally, K2 showed a higher graft survival than K1 (P = 0.023). CONCLUSION Our results agree with a previous study that suggested possible advantages to longer pump times. Both studies should encourage further research into HMP's potential anti-inflammatory effect.
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Affiliation(s)
- Carlos Verdiales
- Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada
| | - Luke Baxter
- College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada
- Canada and Northern Ontario School of Medicine, Thunder Bay, Ontario P7B 5E1, Canada
| | - Hyun Ja Lim
- Department of Community Health and Epidemiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada
| | - Gavin Beck
- Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada
| | - Michael A Moser
- Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan S7N 0W8, Canada
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Kuklinski CA, Blatter JA. Interstitial lung disease as an indication for pediatric lung transplant. Pediatr Pulmonol 2024; 59:2313-2320. [PMID: 38131509 DOI: 10.1002/ppul.26812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 11/09/2023] [Accepted: 12/02/2023] [Indexed: 12/23/2023]
Abstract
Interstitial lung disease can be an indication for lung transplant at any age, but it is a particularly common indication for lung transplant in infants. Nevertheless, not all interstitial lung diseases will lead to lung transplant in childhood. Genetic testing has aided the identification of these diseases in children. In severely affected patients, however, definitive diagnosis is not always necessary to consider referral to a transplant center. At experienced transplant centers, a multidisciplinary team educates patient families and aids in the transplant evaluation of children with interstitial lung disease. Children who have undergone transplant require lifetime immunosuppression and close surveillance, but can enjoy good quality of life for years following surgery.
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Affiliation(s)
- Cadence A Kuklinski
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Joshua A Blatter
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, USA
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Figueroa BA, Ordenana CX, Rezaei M, Said SA, Fahradyan V, Dalla Pozza E, Orfahli LM, Madajka M, Kopparthy V, Papay F, Rampazzo A, Bassiri Gharb B. Orthotopic forelimb transplantation in a Yucatan minipig model: Anatomic and in vivo study. Microsurgery 2024; 44:e31136. [PMID: 38342995 DOI: 10.1002/micr.31136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 09/26/2023] [Accepted: 12/08/2023] [Indexed: 02/15/2024]
Abstract
INTRODUCTION Above elbow transplants represent 19% of the upper extremity transplants. Previous large-animal models have been too distal or heterotopic, did not use immunosuppression and had short survival. We hypothesize that an orthotopic forelimb transplant model, under standard immunosuppression, is feasible and can be used to address questions on peri-transplant ischemia reperfusion injury, and post-transplantation vascular, immunologic, infectious, and functional outcomes. MATERIALS AND METHODS Four forelimbs were used for anatomical studies. Four mock transplants were performed to establish technique/level of muscle/tendon repairs. Four donor and four recipient female Yucatan minipigs were utilized for in-vivo transplants (endpoint 90-days). Forelimbs were amputated at the midarm and preserved through ex vivo normothermic perfusion (EVNP) utilizing an RBC-based perfusate. Hourly perfusate fluid-dynamics, gases, electrolytes were recorded. Contractility during EVNLP was graded hourly using the Medical Research Council scale. EVNP termination criteria included systolic arterial pressure ≥115 mmHg, compartment pressure ≥30 mmHg (at EVNP endpoint), oxygen saturation reduction of 20%, and weight change ≥2%. Indocyanine green (ICG) angiography was performed after revascularization. Limb rejection was evaluated clinically (rash, edema, temperature), and histologically (BANFF classification) collecting per cause and protocol biopsies (POD 1, 7, 30, 60 and endpoint). Systemic infections were assessed by blood culture and tissue histology. CT scan was used to confirm bone bridging at endpoint. RESULTS Animals 2, 4 reached endpoint with grade 0-I rejection. Limbs 1, 3 presented grade III rejection on days 6, 61. CsA troughs averaged 461 ± 189 ng/mL. EVNLP averaged 4.3 ± 0.52 h. Perfusate lactate, PO2 , and pH were 5.6 ± 0.9 mmol/L, 557 ± 72 mmHg and 7.5 ± 0.1, respectively. Muscle contractions were 4 [1] during EVNLP. Transplants 2, 3, 4 showed bone bridging on CT. CONCLUSION We present preliminary evidence supporting the feasibility of an orthotopic, mid-humeral forelimb allotransplantation model under standard immunosuppression regimen. Further research should validate the immunological, infectious, and functional outcomes of this model.
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Affiliation(s)
- Brian A Figueroa
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Carlos X Ordenana
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Majid Rezaei
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Sayf A Said
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Vahe Fahradyan
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Edoardo Dalla Pozza
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Lynn M Orfahli
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Maria Madajka
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Varun Kopparthy
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Frank Papay
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Antonio Rampazzo
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Bahar Bassiri Gharb
- Department of Plastic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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de Fijter J, Dreyer G, Mallat M, Budde K, Pratschke J, Klempnauer J, Zeier M, Arns W, Hugo C, Rump LC, Hauser I, Schenker P, Schiffer M, Grimm MO, Kliem V, Olbricht CJ, Pisarski P, Banas B, Suwelack B, Hakenberg O, Berlakovich G, Schneeberger S, van de Wetering J, Berger S, Bemelman F, Kuypers D, Heidt S, Rahmel A, Claas F, Peeters P, Oberbauer R, Heemann U, Krämer BK. A paired-kidney allocation study found superior survival with HLA-DR compatible kidney transplants in the Eurotransplant Senior Program. Kidney Int 2023; 104:552-561. [PMID: 37343659 DOI: 10.1016/j.kint.2023.05.025] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 03/27/2023] [Accepted: 05/04/2023] [Indexed: 06/23/2023]
Abstract
The Eurotransplant Senior Program (ESP) has expedited the chance for elderly patients with kidney failure to receive a timely transplant. This current study evaluated survival parameters of kidneys donated after brain death with or without matching for HLA-DR antigens. This cohort study evaluated the period within ESP with paired allocation of 675 kidneys from donors 65 years and older to transplant candidates 65 years and older, the first kidney to 341 patients within the Eurotransplant Senior DR-compatible Program and 334 contralateral kidneys without (ESP) HLA-DR antigen matching. We used Kaplan-Meier estimates and competing risk analysis to assess all cause mortality and kidney graft failure, respectively. The log-rank test and Cox proportional hazards regression were used for comparisons. Within ESP, matching for HLA-DR antigens was associated with a significantly lower five-year risk of mortality (hazard ratio 0.71; 95% confidence interval 0.53-0.95) and significantly lower cause-specific hazards for kidney graft failure and return to dialysis at one year (0.55; 0.35-0.87) and five years (0.73; 0.53-0.99) post-transplant. Allocation based on HLA-DR matching resulted in longer cold ischemia (mean difference 1.00 hours; 95% confidence interval: 0.32-1.68) and kidney offers with a significantly shorter median dialysis vintage of 2.4 versus 4.1 yrs. in ESP without matching. Thus, our allocation based on HLA-DR matching improved five-year patient and kidney allograft survival. Hence, our paired allocation study suggests a superior outcome of HLA-DR matching in the context of old-for-old kidney transplantation.
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Affiliation(s)
- Johan de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands.
| | - Geertje Dreyer
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
| | - Marko Mallat
- Department of Nephrology, Leiden University Medical Center, Leiden, Netherlands
| | - Klemens Budde
- Department of Nephrology, Internal Intensive Care Medicine, Campus Charité Mitte, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Jürgen Klempnauer
- Integrated Research and Treatment Centre Transplantation, Hannover Medical School, Hannover, Germany
| | - Martin Zeier
- Department of Nephrology, Heidelberg University Hospital, Heidelberg, Germany
| | - Wolfgang Arns
- Department of Nephrology and Transplantation, Cologne Merheim Medical Center, Cologne, Germany
| | - Christian Hugo
- Clinic for Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany
| | - Lars-Christian Rump
- Department of Internal Medicine/Nephrology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
| | - Ingeborg Hauser
- Department of Nephrology, Goethe University Hospital Frankfurt, Frankfurt/Main, Germany
| | - Peter Schenker
- Department of Surgery, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Mario Schiffer
- Department of Nephrology, Erlangen University Hospital, Erlangen, Germany
| | | | - Volker Kliem
- Department of Internal Medicine and Nephrology, Kidney Transplant Center, Nephrological Center of Lower Saxony, Klinikum Hann, Münden, Germany
| | | | - Przemyslaw Pisarski
- Department of Surgery, Section of Transplant Surgery, Medical Center-University of Freiburg, Freiburg, Germany
| | - Bernhard Banas
- Department of Nephrology, University Hospital Regensburg, Regensburg, Germany
| | - Barbara Suwelack
- Department of Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
| | | | - Gabriela Berlakovich
- Division of Transplantation, Department of Surgery, Medical University of Vienna, Wien, Austria
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | | | - Stefan Berger
- Department of Nephrology, University Medical Center Groningen, Groningen, Netherlands
| | - Frederike Bemelman
- Department of Nephrology, Division of Internal Medicine, Amsterdam University Medical Center, Amsterdam, Netherlands
| | - Dirk Kuypers
- Department of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Sebastiaan Heidt
- Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | - Axel Rahmel
- Eurotransplant International Foundation, Leiden, Netherlands
| | - Frans Claas
- Eurotransplant Reference Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | - Patrick Peeters
- Department of Nephrology, Ghent University Hospital, Ghent, Belgium
| | - Rainer Oberbauer
- Department of Nephrology, Medical University of Vienna, Vienna, Austria
| | - Uwe Heemann
- Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Bernhard K Krämer
- V-th Department of Medicine (Nephrology), University Medical Center Mannheim/University of Heidelberg, Mannheim, Germany
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Halloran PF, Einecke G, Sikosana MLN, Madill-Thomsen K. The Biology and Molecular Basis of Organ Transplant Rejection. Handb Exp Pharmacol 2022; 272:1-26. [PMID: 35091823 DOI: 10.1007/164_2021_557] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Allograft rejection is defined as tissue injury in a transplanted allogeneic organ produced by the effector mechanisms of the adaptive alloimmune response. Effector T lymphocytes and IgG alloantibodies cause two different types of rejection that can occur either individually or simultaneously: T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). In TCMR, cognate effector T cells infiltrate the graft and orchestrate an interstitial inflammatory response in the kidney interstitium in which effector T cells engage antigen-presenting myeloid cells, activating the T cells, antigen-presenting cells, and macrophages. The result is intense expression of IFNG and IFNG-induced molecules, expression of effector T cell molecules and macrophage molecules and checkpoints, and deterioration of parenchymal function. The diagnostic lesions of TCMR follow, i.e. interstitial inflammation, parenchymal deterioration, and intimal arteritis. In ABMR, HLA IgG alloantibodies produced by plasma cells bind to the donor antigens on graft microcirculation, leading to complement activation, margination, and activation of NK cells and neutrophils and monocytes, and endothelial injury, sometimes with intimal arteritis. TCMR becomes infrequent after 5-10 years post-transplant, probably reflecting adaptive mechanisms such as checkpoints, but ABMR can present even decades post-transplant. Some rejection is triggered by inadequate immunosuppression and non-adherence, challenging the clinician to target effective immunosuppression even decades post-transplant.
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Affiliation(s)
- Philip F Halloran
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
| | - Gunilla Einecke
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Majid L N Sikosana
- Division of Nephrology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Iglesias M, Khalifian S, Oh BC, Zhang Y, Miller D, Beck S, Brandacher G, Raimondi G. A short course of tofacitinib sustains the immunoregulatory effect of CTLA4-Ig in the presence of inflammatory cytokines and promotes long-term survival of murine cardiac allografts. Am J Transplant 2021; 21:2675-2687. [PMID: 33331121 DOI: 10.1111/ajt.16456] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 12/07/2020] [Accepted: 12/11/2020] [Indexed: 01/25/2023]
Abstract
Costimulation blockade-based regimens are a promising strategy for management of transplant recipients. However, maintenance immunosuppression via CTLA4-Ig monotherapy is characterized by high frequency of rejection episodes. Recent evidence suggests that inflammatory cytokines contribute to alloreactive T cell activation in a CD28-independent manner, a reasonable contributor to the limited efficacy of CTLA4-Ig. In this study, we investigated the possible synergism of a combined short-term inhibition of cytokine signaling and CD28 engagement on the modulation of rejection. Our results demonstrate that the JAK/STAT inhibitor tofacitinib restored the immunomodulatory effect of CTLA4-Ig on mouse alloreactive T cells in the presence of inflammatory cytokines. Tofacitinib exposure conferred dendritic cells with a tolerogenic phenotype reducing their cytokine secretion and costimulatory molecules expression. JAK inhibition also directly affected T cell activation. In vivo, the combination of CTLA4-Ig and tofacitinib induced long-term survival of heart allografts and, importantly, it was equally effective when using grafts subjected to prolonged ischemia. Transplant survival correlated with a reduction in effector T cells and intragraft accumulation of regulatory T cells. Collectively, our studies demonstrate a powerful synergism between CTLA4-Ig and tofacitinib and suggest their combined use is a promising strategy for improved management of transplanted patients.
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Affiliation(s)
- Marcos Iglesias
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Saami Khalifian
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Byoung C Oh
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Yichuan Zhang
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Devin Miller
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sarah Beck
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Giorgio Raimondi
- Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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9
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Rincon Cintra da Cruz P, Cabral Dias Filho A, Santana VBBM, Biela Boaretto RB, Zanettini Riccetto CL. Donor Age Amplifies the Detrimental Effects of Cold Ischemia Time on Long-Term Kidney Allograft Survival Independently of the Occurrence of Delayed Graft Function or Early Acute Rejection. EXP CLIN TRANSPLANT 2020; 18:436-443. [PMID: 32552628 DOI: 10.6002/ect.2020.0066] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES We investigated the influence of the interaction between donor age and cold ischemia time on allograft survival in the absence of delayed graft function, early acute rejection, or the combination of both. MATERIALS AND METHODS We conducted a retrospective analysis of a cohort of patients first transplanted with living-related and deceased-donor allografts between 2001 and 2016. Predictors included cold ischemia time, donor and recipient age and sex, body mass index, renal replacement therapy duration, cause of end-stage renal disease, HLA class I and II mismatches, panel of reactive antibodies score, donor creatinine concentration, development of delayed graft function, and biopsy-proven acute rejection. The response variable was time until return to renal replacement therapy. Patients who died with functioning allografts were censored at the time of death. Analyses included multivariate Cox proportional hazards regression. RESULTS The study included 498 patients followed for median of 4.1 years with median cold ischemia time of 17.0 hours. On multivariate analysis, allograft survival was negatively affected by the cold ischemia time-donor age interaction (P = .026), acute rejection (P = .043), delayed graft function (P = .001), and acute rejection combined with delayed graft function (P = .002). Restricted mean allograft survival times in patients who developed neither delayed graft function nor acute rejection decreased from 13.6 to 8.6 years when cold ischemia time increased from 12 to 36 hours and donor age increased from 30 to 60 years. CONCLUSIONS Allograft survival was negatively affected by donor age-cold ischemia time interaction independently of the development of delayed graft function, acute rejection, or their combination.
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Affiliation(s)
- Pedro Rincon Cintra da Cruz
- From the Department of Urology and Kidney Transplantation, Base Hospital of the Federal District, Brasília-DF, Brazil
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10
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Gorayeb-Polacchini FS, Caldas HC, Fernandes-Charpiot IMM, Ferreira-Baptista MAS, Gauch CR, Abbud-Filho M. Impact of Cold Ischemia Time on Kidney Transplant: A Mate Kidney Analysis. Transplant Proc 2020; 52:1269-1271. [DOI: 10.1016/j.transproceed.2019.12.052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 12/06/2019] [Indexed: 10/24/2022]
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11
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Dreyer GJ, de Fijter JW. Transplanting the Elderly: Mandatory Age- and Minimal Histocompatibility Matching. Front Immunol 2020; 11:359. [PMID: 32226428 PMCID: PMC7080649 DOI: 10.3389/fimmu.2020.00359] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/14/2020] [Indexed: 12/16/2022] Open
Abstract
Worldwide over 40% of patients receiving renal replacement therapy (RRT) are aged 65 years or older, a number that is still increasing. Renal transplantation is the preferred RRT, providing substantial survival benefit over those remaining on dialysis, including the elderly. Only 3% of patients aged 65 years or older accepted on the waiting list actually received a kidney transplant offer within the Eurotransplant allocation region. To increase the chance for elderly to receive a timely kidney transplant, the Eurotransplant Senior Program was introduced. The ESP supports local allocation of older kidneys to older donors in order to decrease cold ischemia time, while disregarding former exchange principles based on matching for HLA antigens. As a consequence, more elderly received a kidney transplant and a relative higher incidence of acute rejection resulted in additional courses of high steroids and/or depleting antibody therapy. Since death with a functioning graft due to infections is the dominant reason of graft loss in elderly, more intense clinical immunosuppression to prevent or treat acute rejection is not a very attractive option. Therefore in elderly kidney transplant candidates, we advocate reintroduction of minimal histocompatibility criteria (i.e., HLA-DR matching) followed by age-matching with mandatory local/regional allocation to also facilitate short cold ischemia.
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Affiliation(s)
- Geertje J Dreyer
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - Johan W de Fijter
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
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12
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Liu L, Fang C, Fu W, Jiang B, Li G, Qin L, Rosenbluth J, Gong G, Xie CB, Yoo P, Tellides G, Pober JS, Jane-wit D. Endothelial Cell-Derived Interleukin-18 Released During Ischemia Reperfusion Injury Selectively Expands T Peripheral Helper Cells to Promote Alloantibody Production. Circulation 2020; 141:464-478. [PMID: 31744330 PMCID: PMC7035199 DOI: 10.1161/circulationaha.119.042501] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 10/16/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Ischemia reperfusion injury (IRI) predisposes to the formation of donor-specific antibodies, a factor contributing to chronic rejection and late allograft loss. METHODS We describe a mechanism underlying the correlative association between IRI and donor-specific antibodies by using humanized models and patient specimens. RESULTS IRI induces immunoglobulin M-dependent complement activation on endothelial cells that assembles an NLRP3 (NOD-like receptor pyrin domain-containing protein 3) inflammasome via a Rab5-ZFYVE21-NIK axis and upregulates ICOS-L (inducible costimulator ligand) and PD-L2 (programmed death ligand 2). Endothelial cell-derived interleukin-18 (IL-18) selectively expands a T-cell population (CD4+CD45RO+PD-1hiICOS+CCR2+CXCR5-) displaying features of recently described T peripheral helper cells. This population highly expressed IL-18R1 and promoted donor-specific antibodies in response to IL-18 in vivo. In patients with delayed graft function, a clinical manifestation of IRI, these cells were Ki-67+IL-18R1+ and could be expanded ex vivo in response to IL-18. CONCLUSIONS IRI promotes elaboration of IL-18 from endothelial cells to selectively expand alloreactive IL-18R1+ T peripheral helper cells in allograft tissues to promote donor-specific antibody formation.
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Affiliation(s)
- Lufang Liu
- Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Caodi Fang
- Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Whitney Fu
- Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Bo Jiang
- Dept of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Guangxin Li
- Dept of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Lingfeng Qin
- Dept of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | | | | | - Catherine B. Xie
- Dept of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Peter Yoo
- Dept of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | - George Tellides
- Dept of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Jordan S. Pober
- Dept of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Dan Jane-wit
- Division of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
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13
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Said SA, Ordeñana CX, Rezaei M, Figueroa BA, Dasarathy S, Brunengraber H, Rampazzo A, Gharb BB. Ex-Vivo Normothermic Limb Perfusion With a Hemoglobin-Based Oxygen Carrier Perfusate. Mil Med 2020; 185:110-120. [PMID: 32074378 DOI: 10.1093/milmed/usz314] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 08/08/2019] [Accepted: 08/09/2019] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Ex-vivo normothermic limb perfusion (EVNLP) has been proven to preserve limb viability better than standard cold storage. Perfusates containing packed red blood cells (pRBC) improve outcomes when compared to acellular perfusates. Limitations of pRBC-based perfusion include limited availability, need for cross match, mechanical hemolysis, and activation of pro-inflammatory proteins. Hemoglobin-based oxygen carrier (HBOC)-201 (Hemopure) is a solution of polymerized bovine hemoglobin, characterized by low immunogenicity, no risk of hemolytic reaction, and enhanced convective and diffusive oxygen delivery. This is a preliminary study on the feasibility of EVNLP using HBOC-201 as an oxygen carrier. MATERIALS AND METHODS Three porcine forelimb perfusions were performed using an established EVNLP model and an HBOC-201-based perfusate. The perfusion circuit included a roller pump, oxygenator, heat exchanger, and reservoir. Electrolytes, limb temperature, weight, compartment pressure, nerve conduction, and perfusion indicated by indocyanine green angiography and infra-red thermography were monitored. Histological evaluation was performed with hematoxylin and eosin and electron microscopy. RESULTS Three limbs were perfused for 21.3 ± 2.1 hours. Muscle contractility was preserved for 10.6 ± 2.4 hours. Better preservation of the mitochondrial ultrastructure was evident at 12 hours in contrast to crystallization and destruction features in the cold-storage controls. CONCLUSIONS An HBOC-201-EVNLP produced outcomes similar to RBC-EVNLP with preservation of muscle contractility and mitochondrial structure.
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Affiliation(s)
- Sayf A Said
- Cleveland Clinic Foundation, Department of Plastic Surgery, 9500 Euclid Ave, A60, Cleveland, OH 44195
| | - Carlos X Ordeñana
- Cleveland Clinic Foundation, Department of Plastic Surgery, 9500 Euclid Ave, A60, Cleveland, OH 44195
| | - Majid Rezaei
- Cleveland Clinic Foundation, Department of Plastic Surgery, 9500 Euclid Ave, A60, Cleveland, OH 44195
| | - Brian A Figueroa
- Cleveland Clinic Foundation, Department of Plastic Surgery, 9500 Euclid Ave, A60, Cleveland, OH 44195
| | - Srinivasan Dasarathy
- Cleveland Clinic Foundation, Department of Gastroenterology, 9500 Euclid Ave, Cleveland, OH 44195
| | - Henri Brunengraber
- Department of Nutrition, School of Medicine, Case Western Reserve University, 2109 Adelbert Rd, BRB 901, Cleveland, OH 44106
| | - Antonio Rampazzo
- Cleveland Clinic Foundation, Department of Plastic Surgery, 9500 Euclid Ave, A60, Cleveland, OH 44195
| | - Bahar Bassiri Gharb
- Cleveland Clinic Foundation, Department of Plastic Surgery, 9500 Euclid Ave, A60, Cleveland, OH 44195
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14
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Yu MY, Yu BC, Kim YC, Min SI, Ha J, Yang J, Song EY, Kim DK, Joo KW, Ahn C, Kim YS, Lee H. Trend, not severity, of acute kidney injury affects graft outcome in deceased donor kidney transplantation. Clin Transplant 2018; 32:e13431. [DOI: 10.1111/ctr.13431] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/03/2018] [Accepted: 10/14/2018] [Indexed: 12/20/2022]
Affiliation(s)
- Mi-yeon Yu
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
| | - Byung Chul Yu
- Department of Internal Medicine; Soon Chun Hyang University Bucheon Hospital; Bucheon Korea
| | - Yong Chul Kim
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
| | - Sang Il Min
- Department of Surgery; Seoul National University Hospital; Seoul Korea
| | - Jongwon Ha
- Department of Surgery; Seoul National University Hospital; Seoul Korea
- Transplantation center; Seoul National University Hospital; Seoul Korea
| | - Jaeseok Yang
- Department of Surgery; Seoul National University Hospital; Seoul Korea
- Transplantation center; Seoul National University Hospital; Seoul Korea
| | - Eun Young Song
- Department of Laboratory Medicine; Seoul National University Hospital; Seoul Korea
| | - Dong Ki Kim
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
| | - Kwon Wook Joo
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
| | - Curie Ahn
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
| | - Yon Su Kim
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
- Kidney Research Institute, Seoul National University College of Medicine; Seoul Korea
| | - Hajeong Lee
- Department of Internal Medicine; Hanyang University Guri Hospital; Guri Korea
- Department of Internal Medicine; Seoul National University College of Medicine; Seoul Korea
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15
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McFadyen JD, Kiefer J, Braig D, Loseff-Silver J, Potempa LA, Eisenhardt SU, Peter K. Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes. Front Immunol 2018; 9:1351. [PMID: 29946323 PMCID: PMC6005900 DOI: 10.3389/fimmu.2018.01351] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 05/31/2018] [Indexed: 11/26/2022] Open
Abstract
C-reactive protein (CRP) is a member of the pentraxin superfamily that is widely recognized as a marker of inflammatory reactions and cardiovascular risk in humans. Recently, a growing body of data is emerging, which demonstrates that CRP is not only a marker of inflammation but also acts as a direct mediator of inflammatory reactions and the innate immune response. Here, we critically review the various lines of evidence supporting the concept of a pro-inflammatory “CRP system.” The CRP system consists of a functionally inert circulating pentameric form (pCRP), which is transformed to its highly pro-inflammatory structural isoforms, pCRP* and ultimately to monomeric CRP (mCRP). While retaining an overall pentameric structure, pCRP* is structurally more relaxed than pCRP, thus exposing neoepitopes important for immune activation and complement fixation. Thereby, pCRP* shares its pro-inflammatory properties with the fully dissociated structural isoform mCRP. The dissociation of pCRP into its pro-inflammatory structural isoforms and thus activation of the CRP system occur on necrotic, apoptotic, and ischemic cells, regular β-sheet structures such as β-amyloid, the membranes of activated cells (e.g., platelets, monocytes, and endothelial cells), and/or the surface of microparticles, the latter by binding to phosphocholine. Both pCRP* and mCRP can cause activation of platelets, leukocytes, endothelial cells, and complement. The localization and deposition of these pro-inflammatory structural isoforms of CRP in inflamed tissue appear to be important mediators for a range of clinical conditions, including ischemia/reperfusion (I/R) injury of various organs, cardiovascular disease, transplant rejection, Alzheimer’s disease, and age-related macular degeneration. These findings provide the impetus to tackle the vexing problem of innate immunity response by targeting CRP. Understanding the “activation process” of CRP will also likely allow the development of novel anti-inflammatory drugs, thereby providing potential new immunomodulatory therapeutics in a broad range of inflammatory diseases.
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Affiliation(s)
- James D McFadyen
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.,Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia
| | - Jurij Kiefer
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - David Braig
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Julia Loseff-Silver
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Lawrence A Potempa
- College of Pharmacy, Roosevelt University, Schaumburg, IL, United States
| | - Steffen Ulrich Eisenhardt
- Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Medical Faculty of the University of Freiburg, Freiburg, Germany
| | - Karlheinz Peter
- Atherothrombosis and Vascular Biology Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.,Heart Centre, The Alfred Hospital, Melbourne, VIC, Australia.,Department of Immunology, Monash University, Melbourne, VIC, Australia
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16
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Strategies to Reduce Ischemia Reperfusion Injury in Vascularized Composite Allotransplantation of the Limb. J Hand Surg Am 2017; 42:1019-1024. [PMID: 29054354 DOI: 10.1016/j.jhsa.2017.09.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 09/19/2017] [Indexed: 02/02/2023]
Abstract
An important and often underinvestigated contributor to solid organ transplant rejection is ischemia reperfusion injury. This pathophysiological response releases damaging reactive oxygen species and cell stress signals that initiate inflammation, which has a critical role in priming the immune system for allorecognition. In time, this renders graft dysfunction and how this response is mediated in composite tissues remains unknown. Current protocols are drawn from solid organ transplantation with little scientific basis as to how this informs current hand transplantation practices. In addition to preservation flush and allograft cooling, machine perfusion is placing itself experimentally as a concept that could act to promote viability and increase the critical ischemic window, which is especially beneficial at a time of limited donors. With the increasing prevalence worldwide of hand transplantation, we review the potential contribution of ischemia reperfusion injury to hand allograft rejection including both current and experimental strategies.
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17
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Duraes EFR, Madajka M, Frautschi R, Soliman B, Cakmakoglu C, Barnett A, Tadisina K, Liu Q, Grady P, Quintini C, Okamoto T, Papay F, Rampazzo A, Bassiri Gharb B. Developing a protocol for normothermic ex-situ limb perfusion. Microsurgery 2017; 38:185-194. [DOI: 10.1002/micr.30252] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 07/24/2017] [Accepted: 09/18/2017] [Indexed: 11/07/2022]
Affiliation(s)
| | - Maria Madajka
- Plastic Surgery Department; Cleveland Clinic; Cleveland Ohio
| | | | - Basem Soliman
- General Surgery Department; Cleveland Clinic; Cleveland Ohio
| | | | - Addison Barnett
- Plastic Surgery Department; Cleveland Clinic; Cleveland Ohio
| | | | - Qiang Liu
- General Surgery Department; Cleveland Clinic; Cleveland Ohio
| | - Patrick Grady
- Heart and Vascular Institute, Cleveland Clinic; Cleveland Ohio
| | | | | | - Francis Papay
- Plastic Surgery Department; Cleveland Clinic; Cleveland Ohio
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18
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Gai Z, Chu L, Xu Z, Song X, Sun D, Kullak-Ublick GA. Farnesoid X receptor activation protects the kidney from ischemia-reperfusion damage. Sci Rep 2017; 7:9815. [PMID: 28852062 PMCID: PMC5575310 DOI: 10.1038/s41598-017-10168-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 06/16/2017] [Indexed: 02/06/2023] Open
Abstract
Farnesoid X receptor (FXR) activation has been reported to reduce inflammation and oxidative stress. Because both inflammation and oxidative stress are critical for tissue destruction during kidney ischemia reperfusion (I/R) injury, we investigated the protective role of FXR against kidney damage induced by I/R in mice. Mice undergoing renal I/R developed the typical features of acute kidney injury (AKI): increased creatinine, albuminuria, tubular necrosis and apoptosis. Inflammatory cytokine production and oxidative stress were also markedly increased. In mice pretreated with 6-ethyl-chenodeoxycholic acid (6-ECDCA), a selective FXR agonist, I/R induced changes were prevented and renal function and structure were improved. Moreover, FXR activation also effectively prevented the subsequent progression of AKI to chronic kidney disease (CKD) by ameliorating glomerulosclerosis and interstitial fibrosis and by suppressing fibrogenic gene expression. FXR mRNA levels were inversely correlated with the progression to CKD in mice and with the degree of interstitial fibrosis in human biopsies. In further experiments administering 6-ECDCA to renal proximal tubular cells cultured under hypoxia, the renoprotective effects of FXR activation were associated with inhibition of oxidative and ER stress and with increased antioxidant activity. In conclusion, FXR agonists may have a therapeutic role in conditions associated with ischemic kidney damage.
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Affiliation(s)
- Zhibo Gai
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Lei Chu
- Department of Urology, Tengzhou Central People's Hospital, Zaozhuang, People's Republic of China
| | - Zhenqiang Xu
- Department of Cardiovascular Surgery, Shandong Provincial Hospital affiliated to Shandong University, Jinan, People's Republic of China
| | - Xiaoming Song
- Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China
| | - Dongfeng Sun
- Department of Thoracic Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China.
| | - Gerd A Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
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19
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Friedman O, Carmel N, Sela M, Abu Jabal A, Inbal A, Ben Hamou M, Krelin Y, Gur E, Shani N. Immunological and inflammatory mapping of vascularized composite allograft rejection processes in a rat model. PLoS One 2017; 12:e0181507. [PMID: 28746417 PMCID: PMC5528841 DOI: 10.1371/journal.pone.0181507] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 07/03/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Hand and face vascularized composite allotransplantation (VCA) is an evolving and challenging field with great opportunities. During VCA, massive surgical damage is inflicted on both donor and recipient tissues, which may contribute to the high VCA rejection rates. To segregate between the damage-induced and rejection phase of post-VCA responses, we compared responses occurring up to 5 days following syngeneic versus allogeneic vascularized groin flap transplantations, culminating in transplant acceptance or rejection, respectively. METHODS The immune response elicited upon transplantation of a syngeneic versus allogeneic vascularized groin flap was compared at Post-operative days 2 or 5 by histology, immunohistochemistry and by broad-scope gene and protein analyses using quantitative real-time PCR and Multiplex respectively. RESULTS Immune cell infiltration began at the donor-recipient interface and paralleled expression of a large group of wound healing-associated genes in both allografts and syngrafts. By day 5 post-transplantation, cell infiltration spread over the entire allograft but remained confined to the wound site in the syngraft. This shift correlated with upregulation of IL-18, INFg, CXCL9, 10 and 11, CCL2, CCL5, CX3CL1 and IL-10 in the allograft only, suggesting their role in the induction of the anti-alloantigen adaptive immune response. CONCLUSIONS High resemblance between the cues governing VCA and solid organ rejection was observed. Despite this high resemblance we describe also, for the first time, a damage induced inflammatory component in VCA rejection as immune cell infiltration into the graft initiated at the surgical damage site spreading to the entire allograft only at late stage rejection. We speculate that the highly inflammatory setting created by the unique surgical damage during VCA may enhance acute allograft rejection.
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Affiliation(s)
- Or Friedman
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Narin Carmel
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Meirav Sela
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ameen Abu Jabal
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amir Inbal
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Moshe Ben Hamou
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yakov Krelin
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eyal Gur
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nir Shani
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- * E-mail:
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20
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Pileggi A, Molano RD, Berney T, Ichii H, Jose SS, Zahr E, Poggioli R, Linetsky E, Ricordi C, Inverardi L. Prolonged Allogeneic Islet Graft Survival by Protoporphyrins. Cell Transplant 2017; 14:85-96. [DOI: 10.3727/000000005783983160] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Transplantation of islets of Langerhans in patients with type 1 diabetes allows for improved metabolic control and insulin independence. The need for chronic immunosuppression limits this procedure to selected patients with brittle diabetes. Definition of therapeutic strategies allowing permanent engraftment without the need for chronic immunosuppression could overcome such limitations. We tested the effect of the use of protoporphyrins (CoPP and FePP), powerful inducers of the cytoprotective protein hemeoxygenase 1 (HO-1), on allogeneic islet graft survival. Chemically induced diabetic C57BL/6 mice received DBA/2 islets. Treatment consisted in peritransplant administration of CoPP or saline. Islets were either cultured in the presence of FePP or vehicle before implant. Short-course administration of CoPP led to long-term islet allograft survival in a sizable proportion of recipients. Long-term graft-bearing animals rejected third-party islets while accepting a second set donor-specific graft permanently, without additional treatment. Preconditioning of islets with FePP by itself led to improved graft survival in untreated recipients, and provided additional advantage in CoPP-treated recipients, resulting in an increased proportion of long-term surviving grafts. Preconditioning of the graft with protoporphyrins prior to implant resulted in reduction of class II expression. Administration of protoporphyrins to the recipients of allogeneic islets also resulted in transient powerful immunosuppression with reduced lymphocyte proliferative responses, increased proportion of regulatory cells (CD4+CD25+), decreased mononuclear cell infiltrating the graft, paralleled by a systemic upregulation of HO-1 expression. All these mechanisms may have contributed to the induction of donor-specific hyporesponsiveness in a proportion of the protoporphyrintreated animals.
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Affiliation(s)
- Antonello Pileggi
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - R. Damaris Molano
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Thierry Berney
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Hirohito Ichii
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Sergio San Jose
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Elsie Zahr
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Raffaella Poggioli
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Elina Linetsky
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Camillo Ricordi
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
| | - Luca Inverardi
- Cell Transplant Center, Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136
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Influence of Cold Ischemia Time in Kidney Transplants From Small Pediatric Donors. Transplant Direct 2017; 3:e184. [PMID: 28706987 PMCID: PMC5498025 DOI: 10.1097/txd.0000000000000668] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/03/2017] [Indexed: 11/26/2022] Open
Abstract
Background Clinicians may be reluctant to transplant small pediatric kidneys that have prolonged cold ischemia time (CIT) for fear of an additional deleterious effect because pediatric grafts are thought to be more sensitive to ischemia. We aimed to assess the risks associated with transplantation of small pediatric kidneys with prolonged CIT. Methods We performed a retrospective cohort study examining US registry data between 1998 and 2013 of adult first-time kidney-only recipients of small pediatric kidneys from donors weighing 10 to 20 kg, stratified by CIT levels of 0 to 18 (n = 1413), 19 to 30 (n = 1116), and longer than 30 (n = 338) hours. Results All-cause graft survival by CIT groups at 1-year was 92%, 88%, and 89%, respectively. 1-year risk-adjusted graft survival hazard ratios were significantly higher with CIT of 19 to 30 hours (adjusted hazard ratios, 1.37; 95% confidence interval, 1.04-1.81) and somewhat higher with CIT greater than 30 hours (adjusted hazard ratios, 1.24; 95% confidence interval, 0.82-1.88) relative to recipients with CIT 0 to 18 hours. There was little variation in the effect of CIT on graft survival when restricted to single kidney transplants only and no significant interaction of CIT category and single kidney transplantation (P = 0.93). Conclusions Although prolonged CIT is associated with lower early graft survival in small pediatric donor kidney transplants, absolute decreases in 1-year graft survival rates were 3% to 4%.
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22
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Impact of Cold Ischemia Time in Kidney Transplants From Donation After Circulatory Death Donors. Transplant Direct 2017; 3:e177. [PMID: 28706980 PMCID: PMC5498018 DOI: 10.1097/txd.0000000000000680] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 03/31/2017] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Deceased-donor kidneys are exposed to ischemic events from donor instability during the process of donation after circulatory death (DCD). Clinicians may be reluctant to transplant DCD kidneys with prolonged cold ischemia time (CIT) for fear of an additional deleterious effect. METHODS We performed a retrospective cohort study examining US registry data between 1998 and 2013 of adult first-time kidney-only recipients of paired kidneys (derived from the same donor transplanted into different recipients) from DCD donors. RESULTS On multivariable analysis, death-censored graft survival (DCGS) was comparable between recipients of kidneys with higher CIT relative to paired donor recipients with lower CIT when the CIT difference was 1 hour or longer (adjusted hazard ratio, [aHR], 1.02; 95% confidence interval [CI], 0.88-1.17; n = 6276), 5 hours or longer (aHR, 0.98; 95% CI, 0.80-1.19; n = 3130), 10 hours or longer (aHR, 1.15; 95% CI, 0.82-1.60; n = 1124) or 15 hours (aHR, 1.15; 95% CI, 0.66-1.99; n = 498). There was a higher rate of primary non function in the long CIT groups for delta 1 hour or longer (0.89% vs 1.63%; P = 0.006), 5 hours (1.09% vs 1.67%, P = 0.13); 10 hours (0.53% vs 1.78%; P = 0.03), and 15 hours (0.40% vs 1.61%; P = 0.18), respectively. Between each of the 4 delta CIT levels of shorter and longer CIT, there was a significantly and incrementally higher rate of delayed graft function in the long CIT groups for delta 1 hour or longer (37.3% vs 41.7%; P < 0.001), 5 hours (35.9% vs 42.7%; P < 0.001), 10 hours (29.4% vs 44.2%, P < 0.001), and 15 hours (29.6% vs 46.1%, P < 0.001), respectively. Overall patient survival was comparable with delta CITs of 1 hour or longer (aHR, 0.96; 95% CI, 0.84-1.08), 5 hours (aHR, 1.01; 95% CI, 0.85-1.20), and 15 hours (aHR, 1.27; 95% CI, 0.79-2.06) but not 10 hours (aHR, 1.47; 95% CI, 1.09-1.98). CONCLUSIONS These results suggest that in the setting of a prior ischemic donor event, prolonged CIT has limited bearing on long-term outcomes.
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Abstract
Zero-time kidney biopsies, obtained at time of transplantation, are performed in many transplant centers worldwide. Decisions on kidney discard, kidney allocation, and choice of peritransplant and posttransplant treatment are sometimes based on the histological information obtained from these biopsies. This comprehensive review evaluates the practical considerations of performing zero-time biopsies, the predictive performance of zero-time histology and composite histological scores, and the clinical utility of these biopsies. The predictive performance of individual histological lesions and of composite scores for posttransplant outcome is at best moderate. No single histological lesion or composite score is sufficiently robust to be included in algorithms for kidney discard. Dual kidney transplantation has been based on histological assessment of zero-time biopsies and improves outcome in individual patients, but the waitlist effects of this strategy remain obscure. Zero-time biopsies are valuable for clinical and translational research purposes, providing insight in risk factors for posttransplant events, and as baseline for comparison with posttransplant histology. The molecular phenotype of zero-time biopsies yields novel therapeutic targets for improvement of donor selection, peritransplant management and kidney preservation. It remains however highly unclear whether the molecular expression variation in zero-time biopsies could become a better predictor for posttransplant outcome than donor/recipient baseline demographic factors.
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Premise and promise of mesenchymal stem cell-based therapies in clinical vascularized composite allotransplantation. Curr Opin Organ Transplant 2016; 20:608-14. [PMID: 26536421 DOI: 10.1097/mot.0000000000000247] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE OF REVIEW Over the past decade, clinical vascularized composite allotransplantation (VCA) has enabled functional and quality of life restoration in a wide range of indications secondary to devastating tissue loss. However, the spectre of toxicity and long-term complications of chronic immunosuppression has curtailed the momentum of VCA. This study summarizes the literature evidence behind successful mesenchymal stem cell (MSC)-based cell therapies highlighting their multipronged immunomodulatory, restorative and regenerative characteristics with special emphasis towards VCA applications. RECENT FINDINGS Experimental and clinical studies in solid organs and VCA have confirmed that MSCs facilitate immunosuppression-free allograft survival or tolerance, stimulate peripheral nerve regeneration, attenuate ischaemia-reperfusion injury, and improve tissue healing after surgery. It has been hypothesized that MSC-induced long-term operational tolerance in experimental VCA is mediated by induction of mixed donor-specific chimerism and regulatory T-cell mechanisms. All these characteristics of MSCs could thus help expand the scope and clinical feasibility of VCA. SUMMARY Cellular therapies, especially those focusing on MSCs, are emerging in solid organ transplantation including VCA. Although some clinical trials have begun to assess the effects of MSCs in solid organ transplantation, much scientific domain remains uncharted, especially for VCA.
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Tepel M, Beck HC, Tan Q, Borst C, Rasmussen LM. The 82-plex plasma protein signature that predicts increasing inflammation. Sci Rep 2015; 5:14882. [PMID: 26445912 PMCID: PMC4597208 DOI: 10.1038/srep14882] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 09/10/2015] [Indexed: 12/22/2022] Open
Abstract
The objective of the study was to define the specific plasma protein signature that predicts the increase of the inflammation marker C-reactive protein from index day to next-day using proteome analysis and novel bioinformatics tools. We performed a prospective study of 91 incident kidney transplant recipients and quantified 359 plasma proteins simultaneously using nano-Liquid-Chromatography-Tandem Mass-Spectrometry in individual samples and plasma C-reactive protein on the index day and the next day. Next-day C-reactive protein increased in 59 patients whereas it decreased in 32 patients. The prediction model selected and validated 82 plasma proteins which determined increased next-day C-reactive protein (area under receiver-operator-characteristics curve, 0.772; 95% confidence interval, 0.669 to 0.876; P < 0.0001). Multivariable logistic regression showed that 82-plex protein signature (P < 0.001) was associated with observed increased next-day C-reactive protein. The 82-plex protein signature outperformed routine clinical procedures. The category-free net reclassification index improved with 82-plex plasma protein signature (total net reclassification index, 88.3%). Using the 82-plex plasma protein signature increased net reclassification index with a clinical meaningful 10% increase of risk mainly by the improvement of reclassification of subjects in the event group. An 82-plex plasma protein signature predicts an increase of the inflammatory marker C-reactive protein.
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Affiliation(s)
- Martin Tepel
- Department of Nephrology, Odense University Hospital, and University of Southern Denmark, Institute of Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research
| | - Hans C Beck
- Department of Clinical Biochemistry and Pharmacology, Centre for Individualized Medicine in Arterial Diseases (Odense University Hospital), and Centre for Clinical Proteomics (Odense University Hospital/University of Southern Denmark)
| | - Qihua Tan
- Department of Epidemiology, Biostatistics and Biodemography, Institute of Public Health; Unit of Human Genetics, Institute of Clinical Research, University of Southern Denmark
| | - Christoffer Borst
- Department of Nephrology, Odense University Hospital, and University of Southern Denmark, Institute of Molecular Medicine, Cardiovascular and Renal Research, Institute of Clinical Research
| | - Lars M Rasmussen
- Department of Clinical Biochemistry and Pharmacology, Centre for Individualized Medicine in Arterial Diseases (Odense University Hospital), and Centre for Clinical Proteomics (Odense University Hospital/University of Southern Denmark)
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Dreyer GJ, Hemke AC, Reinders MEJ, de Fijter JW. Transplanting the elderly: Balancing aging with histocompatibility. Transplant Rev (Orlando) 2015; 29:205-11. [PMID: 26411382 DOI: 10.1016/j.trre.2015.08.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 08/30/2015] [Accepted: 08/30/2015] [Indexed: 01/10/2023]
Abstract
Across the world, the proportions of senior citizens (i.e. those ≥65years) increase rapidly and are predicted to constitute over 25% of the general population by 2050. In 2012 already 48% of the population with end stage renal disease (ESRD) was aged 65years or older. Transplantation is considered the preferred treatment option for ESRD offering survival advantage over long-term dialysis in the majority of patients. Indeed, acceptable outcomes have been documented for selected patients over the age of 70years or even cases over 80years. The reality of organ scarcity and prolonged waiting times for a deceased donor kidney transplantation, however, indicate that at best 50% of the selected elderly may have realistic expectations to receive a timely transplant offer. By choice or medical selection, access to transplantation also decreases with increasing age. In order to expedite the chance for elderly to receive a kidney transplant dedicated allocation systems have been developed. These allocation systems, like the Eurotransplant Senior Program (ESP), support preferential local allocation of kidneys from older donors to older patients in order to match recipient and graft life while disregarding histocompatibility for HLA antigens. The consequence has been more acute rejection episodes and an increase in immunosuppressive load. In the elderly, the most common cause of graft loss is death with functioning graft and death from infectious diseases is one of the dominant causes. The Eurotransplant Senior DR-compatible Program (ESDP) was designed to further improve the perspective of successful transplantation in the elderly in terms of life and quality of life by re-introducing matching criteria for HLA-DR in the old-for-old algorithm.
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Affiliation(s)
- G J Dreyer
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - A C Hemke
- Nefrovision/Renine, Dutch Transplant Foundation, Leiden, The Netherlands
| | - M E J Reinders
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - J W de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
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Burzynski LC, Humphry M, Bennett MR, Clarke MCH. Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION. J Biol Chem 2015; 290:25188-96. [PMID: 26324711 PMCID: PMC4599021 DOI: 10.1074/jbc.m115.667915] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Indexed: 11/18/2022] Open
Abstract
Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection.
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Affiliation(s)
- Laura C Burzynski
- From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Melanie Humphry
- From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Martin R Bennett
- From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Murray C H Clarke
- From the Division of Cardiovascular Medicine, University of Cambridge, Level 6, Box 110, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
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Peak panel reactive antibody, cancer, graft, and patient outcomes in kidney transplant recipients. Transplantation 2015; 99:1043-50. [PMID: 25539466 DOI: 10.1097/tp.0000000000000469] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND High levels of pretransplant panel reactive antibodies (PRA) are known to be associated with detrimental effects on graft outcomes, but the association between pretransplant PRA levels and long-term patient outcomes is unclear. METHODS Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the risk of rejection, graft failure, mortality and cancer in kidney transplant recipients with varying peak PRA levels. RESULTS In 7,118 kidney transplant recipients between 1997 and 2009, there were a total of 3,171 (44.6%), 3,306 (46.4%), 323 (4.5%), and 318 (4.5%) recipients with peak PRA levels of 0%, 1% to 50%, 51% to 80%, and greater than 80%, respectively. Compared to recipients with 0% peak PRA level, recipients with peak PRA levels greater than 80% were at increased risk of acute rejection (odds ratio, 1.81, 95% confidence interval [95% CI], 1.30-2.35; P < 0.001), death censored graft failure (hazard ratio [HR], 2.06; 95% CI, 1.46-2.91; P < 0.001), all-cause mortality (HR, 1.56; 95% CI, 1.15-2.11; P < 0.001) and cancer (HR, 1.94; 95% CI, 1.26-2.97; P = 0.002) in the adjusted models independent of human leukocyte antigen mismatches and initial immunosuppression. CONCLUSION Highly sensitized kidney transplant recipients with peak PRA greater than 80% had a greater risk of rejection, graft failure, cancer and death independent of age and time on dialysis. Strategies to reduce transplant waiting time and avoidance of sensitization in all potential transplant candidates are imperative to improve the overall graft and patient survival.
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Xia Y, Friedmann P, Cortes CM, Lubetzky ML, Kayler LK. Influence of Cold Ischemia Time in Combination with Donor Acute Kidney Injury on Kidney Transplantation Outcomes. J Am Coll Surg 2015. [DOI: 10.1016/j.jamcollsurg.2015.05.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Pan JSC, Huang L, Belousova T, Lu L, Yang Y, Reddel R, Chang A, Ju H, DiMattia G, Tong Q, Sheikh-Hamad D. Stanniocalcin-1 inhibits renal ischemia/reperfusion injury via an AMP-activated protein kinase-dependent pathway. J Am Soc Nephrol 2014; 26:364-78. [PMID: 25012175 DOI: 10.1681/asn.2013070703] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
AKI is associated with increased morbidity, mortality, and cost of care, and therapeutic options remain limited. Reactive oxygen species are critical for the genesis of ischemic AKI. Stanniocalcin-1 (STC1) suppresses superoxide generation through induction of uncoupling proteins (UCPs), and transgenic overexpression of STC1 inhibits reactive oxygen species and protects from ischemia/reperfusion (I/R) kidney injury. Our observations revealed high AMP-activated protein kinase (AMPK) activity in STC1 transgenic kidneys relative to wild-type (WT) kidneys; thus, we hypothesized that STC1 protects from I/R kidney injury through activation of AMPK. Baseline activity of AMPK in the kidney correlated with the expression of STCs, such that the highest activity was observed in STC1 transgenic mice followed (in decreasing order) by WT, STC1 knockout, and STC1/STC2 double-knockout mice. I/R in WT kidneys increased AMPK activity and the expression of STC1, UCP2, and sirtuin 3. Inhibition of AMPK by administration of compound C before I/R abolished the activation of AMPK, diminished the expression of UCP2 and sirtuin 3, and aggravated kidney injury but did not affect STC1 expression. Treatment of cultured HEK cells with recombinant STC1 activated AMPK and increased the expression of UCP2 and sirtuin 3, and concomitant treatment with compound C abolished these responses. STC1 knockout mice displayed high susceptibility to I/R, whereas pretreatment of STC1 transgenic mice with compound C restored the susceptibility to I/R kidney injury. These data suggest that STC1 is important for activation of AMPK in the kidney, which mediates STC1-induced expression of UCP2 and sirtuin 3 and protection from I/R.
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Affiliation(s)
| | - Luping Huang
- Division of Nephrology, Department of Medicine and
| | | | - Lianghao Lu
- Division of Nephrology, Department of Medicine and
| | - Yongjie Yang
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
| | - Roger Reddel
- Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Sydney, Australia; and
| | - Andy Chang
- Cancer Research Unit, Children's Medical Research Institute, University of Sydney, Sydney, Australia; and
| | - Huiming Ju
- Division of Nephrology, Department of Medicine and
| | - Gabriel DiMattia
- University of Western Ontario, Departments of Oncology and Biochemistry, London Regional Cancer Center, London, Ontario, Canada
| | - Qiang Tong
- Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas
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Yao M, Rogers NM, Csányi G, Rodriguez AI, Ross MA, St Croix C, Knupp H, Novelli EM, Thomson AW, Pagano PJ, Isenberg JS. Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury. J Am Soc Nephrol 2014; 25:1171-86. [PMID: 24511121 PMCID: PMC4033366 DOI: 10.1681/asn.2013040433] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 10/29/2013] [Indexed: 01/08/2023] Open
Abstract
Ischemia reperfusion injury (IRI) causes tissue and organ injury, in part, through alterations in tissue blood flow and the production of reactive oxygen species. The cell surface receptor signal-regulatory protein-α (SIRP-α) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-α in IRI has not been determined. We reported previously that the matricellular protein thrombospondin-1 is upregulated in IRI. Here, we report a novel interaction between thrombospondin-1 and SIRP-α on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-α. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-α and downstream activation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47(phox) (an organizer subunit for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1/2) and increased production of superoxide, both of which were abrogated by knockdown or antibody blockade of SIRP-α. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-α-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-α signaling axis and was associated with increased superoxide production and cell death. A SIRP-α antibody that blocks thrombospondin-1 activation of SIRP-α mitigated the effects of renal IRI, increasing blood flow, suppressing production of reactive oxygen species, and preserving cellular architecture. A role for CD47 in SIRP-α activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-α on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.
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Affiliation(s)
| | | | - Gábor Csányi
- Vascular Medicine Institute, Department of Pharmacology and Chemical Biology
| | - Andres I Rodriguez
- Vascular Medicine Institute, Department of Pharmacology and Chemical Biology
| | | | | | | | | | | | - Patrick J Pagano
- Vascular Medicine Institute, Department of Pharmacology and Chemical Biology
| | - Jeffrey S Isenberg
- Vascular Medicine Institute, Starzl Transplantation Institute, Department of Pharmacology and Chemical Biology, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Erkanli K, Erkanli Senturk G, Aydin U, Arbak S, Ercan F, Tuncdemir M, Isiksacan N, Bakir I. Oxytocin Protects Rat Skeletal Muscle Against Ischemia/Reperfusion Injury. Ann Vasc Surg 2013; 27:662-70. [DOI: 10.1016/j.avsg.2012.10.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2012] [Revised: 10/05/2012] [Accepted: 10/23/2012] [Indexed: 11/28/2022]
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Heinbokel T, Elkhal A, Liu G, Edtinger K, Tullius SG. Immunosenescence and organ transplantation. Transplant Rev (Orlando) 2013; 27:65-75. [PMID: 23639337 PMCID: PMC3718545 DOI: 10.1016/j.trre.2013.03.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2012] [Revised: 12/17/2012] [Accepted: 03/19/2013] [Indexed: 12/22/2022]
Abstract
Increasing numbers of elderly transplant recipients and a growing demand for organs from older donors impose pressing challenges on transplantation medicine. Continuous and complex modifications of the immune system in parallel to aging have a major impact on transplant outcome and organ quality. Both, altered alloimmune responses and increased immunogenicity of organs present risk factors for inferior patient and graft survival. Moreover, a growing body of knowledge on age-dependent modifications of allorecognition and alloimmune responses may require age-adapted immunosuppression and organ allocation. Here, we summarize relevant aspects of immunosenescence and their possible clinical impact on organ transplantation.
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Affiliation(s)
- Timm Heinbokel
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
- Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Abdallah Elkhal
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Guangxiang Liu
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Karoline Edtinger
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Stefan G. Tullius
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
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Cavaillé-Coll M, Bala S, Velidedeoglu E, Hernandez A, Archdeacon P, Gonzalez G, Neuland C, Meyer J, Albrecht R. Summary of FDA workshop on ischemia reperfusion injury in kidney transplantation. Am J Transplant 2013; 13:1134-48. [PMID: 23566221 DOI: 10.1111/ajt.12210] [Citation(s) in RCA: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/24/2013] [Accepted: 01/31/2013] [Indexed: 01/25/2023]
Abstract
The Food and Drug Administration (FDA) held an open public workshop in September 2011 to discuss the current state of science related to the effects of ischemia reperfusion injury (IRI) on outcomes in kidney transplantation. Topics included the development of IRI and delayed graft function (DGF), histology and biomarkers, donor factors, recipient factors, organ quality and organ preservation by means of cold storage solutions or machine perfusion. Various mechanisms of injury and maladaptive response to IRI were discussed as potential targets of intervention. Animal models evaluating specific pathophysiological pathways were presented, as were the limitations of extrapolating animal results to humans. Clinical trials of various drug products administered in the peri-transplant period were summarized; a few demonstrated early improvements in DGF, but none demonstrated an improvement in late graft function. Clinical trial design for IRI and DGF were also discussed.
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Affiliation(s)
- M Cavaillé-Coll
- Division of Transplant and Ophthalmology Products, Office of Antimicrobial Products, Office of New Drugs, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA
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Karadeniz Cerit K, Karakoyun B, Yüksel M, Özkan N, Cetinel Ş, Tolga Dağli E, Yeğen BÇ, Tuğtepe H. The antifibrotic drug halofuginone reduces ischemia/reperfusion-induced oxidative renal damage in rats. J Pediatr Urol 2013; 9:174-83. [PMID: 22373656 DOI: 10.1016/j.jpurol.2012.01.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2011] [Accepted: 01/21/2012] [Indexed: 01/25/2023]
Abstract
AIM The objective of the present study was to evaluate the protective effects of halofuginone against renal ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS Male Wistar albino rats were unilaterally nephrectomized and the left renal pedicles were occluded for 45 min to induce ischemia and then reperfused for 6 h (early) or for 72 h (late). The rats were treated intraperitoneally with either halofuginone (100 μg/kg/day) or saline 30 min prior to ischemia and the dose was repeated in the late reperfusion groups. In the sham groups, rats underwent unilateral nephrectomy and were treated at similar time points. The animals were decapitated at either 6 h or 72 h of reperfusion and trunk blood and kidney samples were obtained. RESULTS I/R injury increased renal malondialdehyde levels, myeloperoxidase activity and reactive oxygen radical levels, and decreased the renal glutathione content. Halofuginone treatment was found to reduce oxidative I/R injury and improve renal function in the rat kidney, as evidenced by reduced generation of reactive oxygen species, depressed lipid peroxidation and myeloperoxidase activity, and increased glutathione levels. CONCLUSIONS The present findings demonstrate the anti-inflammatory and antioxidant effects of halofuginone in renal I/R injury, supporting its potential use where renal I/R injury is inevitable.
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Wu X, Hayes D, Zwischenberger JB, Kuhn RJ, Mansour HM. Design and physicochemical characterization of advanced spray-dried tacrolimus multifunctional particles for inhalation. DRUG DESIGN DEVELOPMENT AND THERAPY 2013; 7:59-72. [PMID: 23403805 PMCID: PMC3569053 DOI: 10.2147/dddt.s40166] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The aim of this study was to design, develop, and optimize respirable tacrolimus microparticles and nanoparticles and multifunctional tacrolimus lung surfactant mimic particles for targeted dry powder inhalation delivery as a pulmonary nanomedicine. Particles were rationally designed and produced at different pump rates by advanced spray-drying particle engineering design from organic solution in closed mode. In addition, multifunctional tacrolimus lung surfactant mimic dry powder particles were prepared by co-dissolving tacrolimus and lung surfactant mimic phospholipids in methanol, followed by advanced co-spray-drying particle engineering design technology in closed mode. The lung surfactant mimic phospholipids were 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-[phosphor-rac-1-glycerol]. Laser diffraction particle sizing indicated that the particle size distributions were suitable for pulmonary delivery, whereas scanning electron microscopy imaging indicated that these particles had both optimal particle morphology and surface morphology. Increasing the pump rate percent of tacrolimus solution resulted in a larger particle size. X-ray powder diffraction patterns and differential scanning calorimetry thermograms indicated that spray drying produced particles with higher amounts of amorphous phase. X-ray powder diffraction and differential scanning calorimetry also confirmed the preservation of the phospholipid bilayer structure in the solid state for all engineered respirable particles. Furthermore, it was observed in hot-stage micrographs that raw tacrolimus displayed a liquid crystal transition following the main phase transition, which is consistent with its interfacial properties. Water vapor uptake and lyotropic phase transitions in the solid state at varying levels of relative humidity were determined by gravimetric vapor sorption technique. Water content in the various powders was very low and well within the levels necessary for dry powder inhalation, as quantified by Karl Fisher coulometric titration. Conclusively, advanced spray-drying particle engineering design from organic solution in closed mode was successfully used to design and optimize solid-state particles in the respirable size range necessary for targeted pulmonary delivery, particularly for the deep lung. These particles were dry, stable, and had optimal properties for dry powder inhalation as a novel pulmonary nanomedicine.
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Affiliation(s)
- Xiao Wu
- University of Kentucky, College of Pharmacy, Department of Pharmaceutical Sciences-Drug Development Division, Lexington, KY 40536-0596 , USA
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Erkanli Senturk G, Erkanli K, Aydin U, Yucel D, Isiksacan N, Ercan F, Arbak S. The protective effect of oxytocin on ischemia/reperfusion injury in rat urinary bladder. Peptides 2013; 40:82-8. [PMID: 23262359 DOI: 10.1016/j.peptides.2012.12.006] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 12/05/2012] [Accepted: 12/05/2012] [Indexed: 11/30/2022]
Abstract
Oxytocin (OXY), a well-known nonapeptide, plays a crucial role in reproduction, and has effects on modulating the immune and inflammatory processes in living organisms as well. Recently it is also known as an antioxidant in several organs. The present study aims to demonstrate the protective effect of OXY against ischemia/reperfusion (I/R) injury in urinary bladder tissue. Abdominal aorta of rats, were clamped to perform urinary bladder ischemia. OXY (0.5 μg/kg) was injected intraperitoneally before ischemia in I/R+OXY group, whereas the vehicle solution was injected to I/R group. At the end of reperfusion, tissue samples from urinary bladder were processed for histochemical, ultrastructural and biochemical analysis. Tissue sections were stained by toluidine blue for mast cell counting and hematoxylin-eosin for histopathology. In addition, malondialdehyde (MDA) and glutathione (GSH) levels were determined biochemically. The results demonstrated that there was an extreme damage at urothelium, dilatation of intercellular junctions, inflammatory cell infiltration in I/R group. I/R+OXY group demonstrated a reduction in the severity of urinary bladder damage. According to mast cell counting results, both granulated and degranulated mast cells were decreased in I/R+OXY group compared to I/R group. The mean MDA level was higher in I/R group compared to control and lower in I/R+OXY group compared to I/R group. GSH level reduced in I/R group compared to the control and increased in I/R+OXY group compared to I/R group. In conclusion, oxytocin, as confirmed by histological evaluation and biochemical assays has a potential protective effect in the urinary bladder tissue against ischemia/reperfusion injury.
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Affiliation(s)
- G Erkanli Senturk
- Acibadem University, School of Medicine, Department of Histology and Embryology, Istanbul, Turkiye.
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38
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39
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Naesens M, Kuypers DRJ, De Vusser K, Vanrenterghem Y, Evenepoel P, Claes K, Bammens B, Meijers B, Lerut E. Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure. Am J Transplant 2013; 13:86-99. [PMID: 23136888 DOI: 10.1111/j.1600-6143.2012.04304.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 08/15/2012] [Accepted: 08/30/2012] [Indexed: 01/25/2023]
Abstract
The impact of early histological lesions of renal allografts on long-term graft survival remains unclear. We included all renal allograft recipients transplanted at a single center from 1991 to 2001 (N = 1197). All indication biopsies performed within the first year after transplantation were rescored according to the current Banff classification. Mean follow-up time was 14.8 ± 2.80 years. In multivariate Cox proportional hazards analysis, arteriolar hyalinosis and transplant glomerulopathy were independently associated with death-censored graft survival, adjusted for baseline demographic covariates. Arteriolar hyalinosis correlated with interstitial fibrosis, tubular atrophy, mesangial matrix increase, vascular intimal thickening and glomerulosclerosis. Clustering of the patients according to these chronic lesions, reflecting the global burden of chronic injury, associated better with long-term graft survival than each of the chronic lesions separately. Early chronic histological damage was an independent risk factor for late graft loss, irrespective whether a specific, progressive disease was diagnosed or not, while T cell-mediated rejection did not. We conclude that individual chronic lesions like arteriolar hyalinosis, tubular atrophy, interstitial fibrosis, glomerulosclerosis, mesangial matrix increase and vascular intimal thickening cannot be seen as individual entities. The global burden of early chronic histological damage within the first year after transplantation importantly affects the fate of the allografts.
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Affiliation(s)
- M Naesens
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium, EU.
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40
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Khalifian S, Broyles JM, Tuffaha SH, Alrakan M, Ibrahim Z, Sarhane KA. Immune mechanisms of ischemia-reperfusion injury in transplantation. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/oji.2013.33020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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41
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Heinbokel T, Hock K, Liu G, Edtinger K, Elkhal A, Tullius SG. Impact of immunosenescence on transplant outcome. Transpl Int 2012. [DOI: 10.1111/tri.12013] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | | | - Guangxiang Liu
- Transplant Surgery Research Laboratory and Division of Transplant Surgery; Brigham and Women's Hospital; Harvard Medical School; Boston; MA; USA
| | - Karoline Edtinger
- Transplant Surgery Research Laboratory and Division of Transplant Surgery; Brigham and Women's Hospital; Harvard Medical School; Boston; MA; USA
| | - Abdallah Elkhal
- Transplant Surgery Research Laboratory and Division of Transplant Surgery; Brigham and Women's Hospital; Harvard Medical School; Boston; MA; USA
| | - Stefan G. Tullius
- Transplant Surgery Research Laboratory and Division of Transplant Surgery; Brigham and Women's Hospital; Harvard Medical School; Boston; MA; USA
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Acute kidney injury: a conspiracy of Toll-like receptor 4 on endothelia, leukocytes, and tubules. Pediatr Nephrol 2012; 27:1847-54. [PMID: 22033798 PMCID: PMC3523189 DOI: 10.1007/s00467-011-2029-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 08/31/2011] [Accepted: 09/01/2011] [Indexed: 01/08/2023]
Abstract
Ischemic acute kidney injury (AKI) contributes to considerable morbidity and mortality in hospitalized patients and can contribute to rejection during kidney transplantation. Maladaptive immune responses can exacerbate injury, and targeting these responses holds promise as therapy for AKI. In the last decade, a number of molecules and receptors were identified in the innate immune response to ischemia-reperfusion injury. This review primarily focuses on one pathway that leads to maladaptive inflammation: toll-like receptor 4 (TLR4) and one of its ligands, high mobility group box protein 1 (HMGB1). The temporal-spatial roles and potential therapeutics targeting this particular receptor-ligand interaction are also explored.
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43
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Rogers NM, Stephenson MD, Kitching AR, Horowitz JD, Coates PTH. Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells. Br J Pharmacol 2012; 166:194-209. [PMID: 21745189 DOI: 10.1111/j.1476-5381.2011.01590.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE Renal ischaemia-reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway. EXPERIMENTAL APPROACH We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting. KEY RESULTS Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein. CONCLUSIONS AND IMPLICATIONS Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury.
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Affiliation(s)
- N M Rogers
- Transplant Immunology Laboratory, Hanson Institute, Adelaide, SA, Australia
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Rogers NM, Thomson AW, Isenberg JS. Activation of parenchymal CD47 promotes renal ischemia-reperfusion injury. J Am Soc Nephrol 2012; 23:1538-50. [PMID: 22859854 DOI: 10.1681/asn.2012020137] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ischemia-reperfusion injury (IRI) contributes to decreased allograft function and allograft rejection in transplanted kidneys. Thrombospondin-1 is a stress protein typically secreted in response to hypoxia and the ligand activator for the ubiquitously expressed receptor CD47. The function of activated CD47 in IRI remains completely unknown. Here, we found that both CD47 and its ligand thrombospondin-1 were upregulated after renal IRI in mice. CD47-knockout mice were protected against renal dysfunction and tubular damage, suggesting that the development of IRI requires intact CD47 signaling. Chimeric CD47-knockout mice engrafted with wild-type hematopoietic cells had significantly lower serum creatinine and less tubular damage than wild-type controls after IRI, suggesting that CD47 signaling in parenchymal cells predominantly mediates renal damage. Treatment with a CD47-blocking antibody protected mice from renal dysfunction and tubular damage compared with an isotype control. Taken together, these data imply that CD47 on parenchymal cells promotes injury after renal ischemia and reperfusion. Therefore, CD47 blockade may have therapeutic potential to prevent or suppress ischemia-reperfusion-mediated damage.
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Affiliation(s)
- Natasha M Rogers
- Division of Pulmonary Allergy and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh School of Medicine, E1240 Biomedical Science Tower, Room E1258, 200 Lothrop Street, Pittsburgh, PA 15261, USA
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45
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Overexpression of stanniocalcin-1 inhibits reactive oxygen species and renal ischemia/reperfusion injury in mice. Kidney Int 2012; 82:867-77. [PMID: 22695329 PMCID: PMC3443530 DOI: 10.1038/ki.2012.223] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Reactive oxygen species, endothelial dysfunction, inflammation, and mitogen-activated protein kinases have important roles in the pathogenesis of ischemia/reperfusion kidney injury. Stanniocalcin-1 (STC1) suppresses superoxide generation in many systems through induction of mitochondrial uncoupling proteins and blocks the cytokine-induced rise in endothelial permeability. Here we tested whether transgenic overexpression of STC1 protects from bilateral ischemia/reperfusion kidney injury. This injury in wild type mice caused a halving of the creatinine clearance; severe tubular vacuolization and cast formation; increased infiltration of macrophages and T cells; higher vascular permeability; greater production of superoxide and hydrogen peroxide; and higher ratio of activated ERK/activated JNK and p38, all compared to sham-treated controls. Mice transgenic for human STC1 expression, however, had resistance to equivalent ischemia/reperfusion injury indicated as no significant change from controls in any of these parameters. Tubular epithelial cells in transgenic mice expressed higher mitochondrial uncoupling protein 2 and lower superoxide generation. Pre-treatment of transgenic mice with paraquat, a generator of reactive oxygen species, before injury restored the susceptibility to ischemia/reperfusion kidney injury, suggesting that STC1 protects by an anti-oxidant mechanism. Thus, STC1 may be a therapeutic target for ischemia/reperfusion kidney injury.
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46
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47
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Lim WH, Dogra G, Chadban SJ, Campbell SB, Clayton P, Cohney S, Russ GR, McDonald SP. Lack of impact of donor age on patient survival for renal transplant recipients ≥60years. Transpl Int 2012; 25:401-8. [PMID: 22340432 DOI: 10.1111/j.1432-2277.2012.01429.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
There has been an increase in the number of older patients on the transplant waiting list and acceptance of older donor kidneys. Although kidneys from older donors have been associated with poorer graft outcomes, whether there is a differential impact of donor age on outcomes in older recipients remains unclear. The aim of this study was to evaluate the effect of donor age on graft and patient survival in renal transplant (RT) recipients ≥60years. Using the Australia and New Zealand Dialysis and Transplant Registry, outcomes of 1,037 RT recipients ≥60years between 1995 and 2009 were analyzed. Donor age groups were categorized into 0-20, >20-40, >40-60, and >60years. Compared with recipients receiving donor kidneys >60years, those receiving donor kidneys >20-40years had lower risk of acute rejection (odds ratio 0.46, 95% CI 0.27, 0.79; P<0.01) and death-censored graft failure (HR 0.37, 95% CI 0.19, 0.72; P<0.01). There was no association between donor age groups and death. With a corresponding growth in the availability of older donor kidneys and the observed lack of association between donor age and patient survival in RT recipients ≥60years, preferential allocation of older donor kidneys to RT recipients ≥60years may not disadvantage the life expectancy of these patients.
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Affiliation(s)
- Wai H Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia.
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48
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Kayler LK, Magliocca J, Zendejas I, Srinivas TR, Schold JD. Impact of cold ischemia time on graft survival among ECD transplant recipients: a paired kidney analysis. Am J Transplant 2011; 11:2647-56. [PMID: 21906257 DOI: 10.1111/j.1600-6143.2011.03741.x] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Delays in expanded criteria donor (ECD) kidney placement increases cold ischemia times (CIT) potentially leading to discard. The effect of increased CIT on ECD kidney transplant outcomes is unknown. We evaluated paired ECD kidneys (derived from the same donor transplanted to different recipients) from the SRTR registry transplanted between 1995 and 2009 (n = 17,514). To test the effect of CIT, we excluded paired transplants with the same CIT (n = 3286). Of 14,230 recipients (7115 donors) the median difference in CIT was 5 h (Q1 = 3 h, Q3 = 9 h). Delayed graft function (DGF) was significantly more likely between pairs with greater CIT (35% vs. 31%, p < 0.001) including substantially higher rates for CIT differences ≥ 15 h (42%). Overall graft loss was not significantly different between recipients with higher CIT relative to paired donor recipients with lower CIT (p = 0.47) or for pairs with differences of 1-3 h (p = 0.90), 4-9 h (p = 0.41), 10-14 h (p = 0.36) or ≥ 15 h (p = 0.10). Results were consistent in multivariable models adjusted for recipient factors. Although increasing cold ischemia time is a risk factor for DGF among ECD kidney transplants, there is no effect on graft survival which may suggest an important utility for donor kidneys that may not currently be considered viable.
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Affiliation(s)
- L K Kayler
- Shands Hospital at the University of Florida Gainesville, FL, USA.
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Kayler LK, Srinivas TR, Schold JD. Influence of CIT-induced DGF on kidney transplant outcomes. Am J Transplant 2011; 11:2657-64. [PMID: 22051325 DOI: 10.1111/j.1600-6143.2011.03817.x] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Increased cold ischemia time (CIT) predisposes to delayed graft function (DGF). DGF is considered a risk factor for graft failure after kidney transplantation, but DGF has multiple etiologies. To analyze the risk of CIT-induced DGF on graft survival, we evaluated paired deceased-donor kidneys (derived from the same donor transplanted to different recipients) in which one donor resulted in DGF and the other did not, using national Scientific Registry of Transplant Recipients data between 2000 and 2009. Of 54 565 kidney donors, 15 833 were excluded for mate kidney non-transplantation, 27 340 because both or neither kidney developed DGF and 2310 for same/unknown CIT. The remaining 9082 donors (18 164 recipients) were analyzed. The adjusted odds (aOR) of DGF were significantly higher when CIT was longer by ≥ 1 h (aOR 1.81, 95% CI 1.7-2.0), ≥ 5 h (aOR 2.5, 95% CI 2.3-2.9), ≥ 10 h (aOR 3.3, 95% CI 2.7-2.9) and ≥ 15 h (aOR 4.4, 95% CI 3.4-5.8) compared to shorter CIT transplants. In the multivariable models adjusted for recipient characteristics, graft survival between paired donor transplants, with and without DGF, were similar. These results suggest that DGF, specifically induced by prolonged CIT, has limited bearing on long-term outcomes, which may have important implications for kidney utilization.
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Affiliation(s)
- L K Kayler
- Montefiore Medical Center, Bronx, NY, USA.
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50
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Fogal B, Yi T, Wang C, Rao DA, Lebastchi A, Kulkarni S, Tellides G, Pober JS. Neutralizing IL-6 reduces human arterial allograft rejection by allowing emergence of CD161+ CD4+ regulatory T cells. THE JOURNAL OF IMMUNOLOGY 2011; 187:6268-80. [PMID: 22084439 DOI: 10.4049/jimmunol.1003774] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Perioperative injuries to an allograft exacerbate graft rejection, which in humans is primarily mediated by effector memory T cells. IL-6 transcripts in human coronary artery segments rapidly increase posttransplantation into immunodeficient mouse hosts compared with those of pretransplant specimens and fall dramatically by 30 d. Adoptive transfer of human PBMCs allogeneic to the artery 2 d postoperatively results in T cell infiltrates and intimal expansion 4 wk later. Ab neutralization of human IL-6 reduces the magnitude of intimal expansion and total T cell infiltration but increases the relative expression of CD161 while decreasing other Th17 markers. Coculture of MHC class II-expressing human endothelial cells (ECs) with allogeneic CD4(+) memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC cocultures results in enhanced T cell proliferation of CD161(+) CD4(+) T cells, reduces total T cell proliferation upon restimulation in secondary cultures (an effect dependent on CD161(+) T cells), increases expression of FOXP3 in CD161(+) T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161(+) regulatory T cells.
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Affiliation(s)
- Birgit Fogal
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
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