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1
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Custódio G, Massutti AM, da Igreja MR, Lemos NE, Crispim D, Visioli F, Palma VDM, Leitão CB, Rech TH. Does liraglutide alleviate inflammation in brain-dead donors? A randomized clinical trial. Liver Transpl 2024; 30:607-617. [PMID: 37938130 DOI: 10.1097/lvt.0000000000000298] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 10/14/2023] [Indexed: 11/09/2023]
Abstract
Brain death triggers an inflammatory cascade that damages organs before procurement, adversely affecting the quality of grafts. This randomized clinical trial aimed to compare the efficacy of liraglutide compared to placebo in attenuating brain death-induced inflammation, endoplasmic reticulum stress, and oxidative stress. We conducted a double-blinded, placebo-controlled, randomized clinical trial with brain-dead donors. Fifty brain-dead donors were randomized to receive subcutaneous liraglutide or placebo. The primary outcome was the reduction in IL-6 plasma levels. Secondary outcomes were changes in other plasma pro-inflammatory (IL-1β, interferon-γ, TNF) and anti-inflammatory cytokines (IL-10), expression of antiapoptotic ( BCL2 ), endoplasmic reticulum stress markers ( DDIT3/CHOP , HSPA5/BIP ), and antioxidant ( superoxide dismutase 2 , uncoupling protein 2 ) genes, and expression TNF, DDIT3, and superoxide dismutase 2 proteins in liver biopsies. The liraglutide group showed lower cytokine levels compared to the placebo group during follow-up: Δ IL-6 (-28 [-182, 135] vs. 32 [-10.6, 70.7] pg/mL; p = 0.041) and Δ IL-10 (-0.01 [-2.2, 1.5] vs. 1.9 [-0.2, 6.1] pg/mL; p = 0.042), respectively. The administration of liraglutide did not significantly alter the expression of inflammatory, antiapoptotic, endoplasmic reticulum stress, or antioxidant genes in the liver tissue. Similar to gene expression, expressions of proteins in the liver were not affected by the administration of liraglutide. Treatment with liraglutide did not increase the organ recovery rate [OR = 1.2 (95% CI: 0.2-8.6), p = 0.82]. Liraglutide administration reduced IL-6 and prevented the increase of IL-10 plasma levels in brain-dead donors without affecting the expression of genes and proteins related to inflammation, apoptosis, endoplasmic reticulum stress, or oxidative stress.
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Affiliation(s)
- Geisiane Custódio
- Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Intensive Care Unit, Hospital Santa Isabel, Blumenau, SC, Brazil
| | | | | | - Natália Emerim Lemos
- Diabetes and Metabolism Group, Centro de Pesquisa Clínica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Daisy Crispim
- Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Diabetes and Metabolism Group, Centro de Pesquisa Clínica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Fernanda Visioli
- Department of Oral Pathology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Victor de Mello Palma
- Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Cristiane Bauermann Leitão
- Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Diabetes and Metabolism Group, Centro de Pesquisa Clínica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Tatiana Helena Rech
- Graduate Program in Medical Sciences: Endocrinology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Diabetes and Metabolism Group, Centro de Pesquisa Clínica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
- School of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
- Intensive Care Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
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2
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Salvadori M, Tsalouchos A. Histological and clinical evaluation of marginal donor kidneys before transplantation: Which is best? World J Transplant 2019; 9:62-80. [PMID: 31523629 PMCID: PMC6715576 DOI: 10.5500/wjt.v9.i4.62] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/21/2019] [Accepted: 07/30/2019] [Indexed: 02/05/2023] Open
Abstract
Organ shortage represents one of the major limitations to the development of kidney transplantation. To increase the donor pool and to answer the ever increasing kidney request, physicians are recurring to marginal kidneys as kidneys from older donors, from hypertensive or diabetic donors and from non-heart beating donors. These kidneys are known to have frequently a worse outcome in the recipients. To date major problem is to evaluate such kidneys in order to use or to discard them before transplantation. The use of such kidneys create other relevant question as whether to use them as single or dual transplant and to allocate them fairly according transplant programs. The pre-transplant histological evaluation, the clinical evaluation of the donor or both the criteria joined has been used and according the time each criterion prevailed over the others. Aim of this review has been to examine the advantages and the drawbacks of any criterion and how they have changed with time. To date any criterion has several limitations and several authors have argued for the development of new guidelines in the field of the kidney evaluation for transplantation. Several authors argue that the use of omic technologies should improve the organ evaluation and studies are ongoing to evaluate these technologies either in the donor urine or in the biopsies taken before transplantation.
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Affiliation(s)
- Maurizio Salvadori
- Department of Transplantation Renal Unit, Careggi University Hospital, viale Pieraccini 18, Florence 50139, Italy
| | - Aris Tsalouchos
- Nephrology and Dialysis Unit, Saints Cosmas and Damian Hospital, Via Cesare Battisti, Pescia (PT) 2-51017, Italy
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3
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Weaver JL, Schucht JE, Matheson PJ, Matheson AJ, Ghazi CA, Downard CD, Garrison RN, Smith JW. Direct Peritoneal Resuscitation Reduces Lung Injury and Caspase 8 Activity in Brain Death. J INVEST SURG 2019; 33:803-812. [PMID: 30907191 DOI: 10.1080/08941939.2019.1579274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Background: Acute brain death (ABD) is associated with inflammation and lung injury. Direct peritoneal resuscitation (DPR) improves blood flow to the vital organs after ABD. DPR reduces lung injury, but the mechanism for this is unknown. Methods: Male Sprague-Dawley rats were randomized to five groups (n = 8/group): (1) Sham (no ABD); (2) Targeted intravenous fluid (TIVF) (ABD plus enough IVF to maintain a MAP of 80 mmHg) at 2 hours post-resuscitation (RES); (3) ABD + TIVF + DPR (TIVF and 30 cc intraperitoneal 2.5% Delflex) at 2 hours post-RES; (4) ABD + TIVF at 4 hours post-RES; and (5) ABD + TIVF + DPR at 4 hours post-RES. Messenger RNA (mRNA) levels were measured using Qiagen qRT PCR. Protein levels were assessed using quantitative ELISAs and the Luminex MagPix system. Results: Use of DPR caused 5.8-fold downregulation of mRNA expression for TNF-α and 2.7-fold decrease for the TNF receptor compared to TIVF alone. Caspase 8 mRNA was also downregulated. Protein levels for TNF-α, TNF receptor, caspase 8, NFκB, and NFκB inhibitor kinase, which promotes dissociation of NFκB inhibitor, were reduced by DPR. Cell death markers M30 and M65 were also decreased with DPR. Conclusions: Use of DPR caused changes in the expression of multiple mRNAs and proteins in the caspase 8 apoptotic pathway. These data represent a mechanism through which DPR exerts its beneficial effects within the lung tissue.
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Affiliation(s)
- Jessica L Weaver
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Jessica E Schucht
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Paul J Matheson
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Amy J Matheson
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Cameron A Ghazi
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Cynthia D Downard
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Richard Neal Garrison
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
| | - Jason W Smith
- Department of Surgery, University of Louisville, Louisville, KY, USA.,Robley Rex Veterans Affairs Medical Center, Louisville, KY, USA
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4
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Lemos NE, Dieter C, Carlessi R, Rheinheimer J, Brondani LDA, Leitão CB, Bauer AC, Crispim D. Renal effects of exendin-4 in an animal model of brain death. Mol Biol Rep 2019; 46:2197-2207. [PMID: 30759298 DOI: 10.1007/s11033-019-04674-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/05/2019] [Indexed: 12/14/2022]
Abstract
Organ transplantation is the gold standard therapy for the majority of patients with terminal organ failure. However, it is still a limited treatment especially due to the low number of brain death (BD) donors in relation to the number of waiting list recipients. Strategies to increase the quantity and quality of donor organs have been studied, and the administration of exendin-4 (Ex-4) to the donor may be a promising approach. Male Wistar rats were randomized into 3 groups: (1) control, without central nervous system injury; (2) BD induced experimentally, and (3) BD induced experimentally + Ex-4 administered immediately after BD induction. After BD induction, animals were monitored for 6 h before blood collection and kidney biopsy. Kidney function was assessed by biochemical quantification of plasma kidney markers. Gene and protein expressions of inflammation- and stress-related genes were evaluated by RT-qPCR and immunoblot analysis. Animals treated with Ex-4 had lower creatinine and urea levels compared with controls. BD induced oxidative stress in kidney tissue through increased expression of Ucp2, Sod2 and Inos, and Ex-4 administration reduced the expression of these genes. Ex-4 also induced increased expression of the anti-apoptotic Bcl2 gene. Nlrp3 and Tnf expressions were up-regulated in the BD group compared with controls, but Ex-4 treatment had no effect on these genes. Our findings suggest that Ex-4 administration in BD rats reduces BD-induced kidney damage by decreasing the expression of oxidative stress genes and increasing the expression of Bcl2.
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Affiliation(s)
- Natália Emerim Lemos
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil
| | - Cristine Dieter
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil
| | - Rodrigo Carlessi
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Kent St., Bentley, Perth, WA, 6102, Australia
| | - Jakeline Rheinheimer
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil
| | - Letícia de Almeida Brondani
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil
| | - Cristiane Bauermann Leitão
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil
| | - Andrea Carla Bauer
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil.,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil.,Nephrology Division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande Do Sul, Brazil
| | - Daisy Crispim
- Laboratory of Human Pancreatic Islet Biology, Endocrine Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, prédio 12, 4° andar, Porto Alegre, Rio Grande Do Sul, 90035-003, Brazil. .,Postgraduation Program in Medical Sciences: Endocrinology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande Do Sul, Brazil.
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A porcine model to study the effect of brain death on kidney genomic responses. J Clin Transl Sci 2018; 2:208-216. [PMID: 30800478 PMCID: PMC6374499 DOI: 10.1017/cts.2018.312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Revised: 05/17/2018] [Accepted: 05/26/2018] [Indexed: 11/16/2022] Open
Abstract
Introduction A majority of transplanted organs come from donors after brain death (BD). Renal grafts from these donors have higher delayed graft function and lower long-term survival rates compared to living donors. We designed a novel porcine BD model to better delineate the incompletely understood inflammatory response to BD, hypothesizing that adhesion molecule pathways would be upregulated in BD. Methods Animals were anesthetized and instrumented with monitors and a balloon catheter, then randomized to control and BD groups. BD was induced by inflating the balloon catheter and animals were maintained for 6 hours. RNA was extracted from kidneys, and gene expression pattern was determined. Results In total, 902 gene pairs were differently expressed between groups. Eleven selected pathways were upregulated after BD, including cell adhesion molecules. Conclusions These results should be confirmed in human organ donors. Treatment strategies should target involved pathways and lessen the negative effects of BD on transplantable organs.
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6
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Agrawal L, Engel KB, Greytak SR, Moore HM. Understanding preanalytical variables and their effects on clinical biomarkers of oncology and immunotherapy. Semin Cancer Biol 2017; 52:26-38. [PMID: 29258857 DOI: 10.1016/j.semcancer.2017.12.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 12/07/2017] [Accepted: 12/13/2017] [Indexed: 12/20/2022]
Abstract
Identifying a suitable course of immunotherapy treatment for a given patient as well as monitoring treatment response is heavily reliant on biomarkers detected and quantified in blood and tissue biospecimens. Suboptimal or variable biospecimen collection, processing, and storage practices have the potential to alter clinically relevant biomarkers, including those used in cancer immunotherapy. In the present review, we summarize effects reported for immunologically relevant biomarkers and highlight preanalytical factors associated with specific analytical platforms and assays used to predict and gauge immunotherapy response. Given that many of the effects introduced by preanalytical variability are gene-, transcript-, and protein-specific, biospecimen practices should be standardized and validated for each biomarker and assay to ensure accurate results and facilitate clinical implementation of newly identified immunotherapy approaches.
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Affiliation(s)
- Lokesh Agrawal
- Biorepositories and Biospecimen Research Branch (BBRB), Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Drive, Bethesda, Maryland, USA
| | | | | | - Helen M Moore
- Biorepositories and Biospecimen Research Branch (BBRB), Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, 9609 Medical Center Drive, Bethesda, Maryland, USA.
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7
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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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8
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Kamińska D, Kościelska-Kasprzak K, Chudoba P, Hałoń A, Mazanowska O, Gomółkiewicz A, Dzięgiel P, Drulis-Fajdasz D, Myszka M, Lepiesza A, Polak W, Boratyńska M, Klinger M. The influence of warm ischemia elimination on kidney injury during transplantation - clinical and molecular study. Sci Rep 2016; 6:36118. [PMID: 27808277 PMCID: PMC5093711 DOI: 10.1038/srep36118] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 10/11/2016] [Indexed: 11/21/2022] Open
Abstract
Kidney surface cooling was used during implantation to assess the effect of warm ischemia elimination on allograft function, histological changes and immune-related gene expression. 23 recipients were randomly assigned to a group operated on with kidney surface cooling during implantation (ice bag technique, IBT group), and the other 23 recipients receiving the contralateral kidney from the same donor were operated on with a standard technique. Three consecutive kidney core biopsies were obtained during the transplantation procedure: after organ recovery, after cold ischemia and after reperfusion. Gene expression levels were determined using low-density arrays (Format 32, TaqMan). The IBT group showed a significantly lower rate of detrimental events (delayed graft function and/or acute rejection, p = 0.015) as well as higher glomerular filtration rate on day 14 (p = 0.026). A greater decrease of MMP9 and LCN2 gene expression was seen in the IBT group during total ischemia (p = 0.003 and p = 0.018). Elimination of second warm ischemia reduced the number of detrimental events after kidney transplantation, and thus had influence on the short-term but not long-term allograft function. Surface cooling of the kidney during vascular anastomosis may reduce some detrimental effects of immune activation resulting from both brain death and ischemia-reperfusion injury.
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Affiliation(s)
- Dorota Kamińska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław 50-556, Poland
| | | | - Paweł Chudoba
- Department of General, Vascular and Transplant Surgery, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Agnieszka Hałoń
- Department of Pathomorphology and Oncological Cytology, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Oktawia Mazanowska
- Faculty of Medicine and Dentistry, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Agnieszka Gomółkiewicz
- Department of Histology and Embryology, Wroclaw Medical University, 50-368, Wrocław, Poland
| | - Piotr Dzięgiel
- Department of Histology and Embryology, Wroclaw Medical University, 50-368, Wrocław, Poland
| | - Dominika Drulis-Fajdasz
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Marta Myszka
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Agnieszka Lepiesza
- Department of General, Vascular and Transplant Surgery, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Wojciech Polak
- Department of Surgery, Division of HPB and Transplantation Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maria Boratyńska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław 50-556, Poland
| | - Marian Klinger
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wrocław 50-556, Poland
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Impact of brain death on ischemia/reperfusion injury in liver transplantation. Curr Opin Organ Transplant 2014; 19:108-14. [PMID: 24565958 DOI: 10.1097/mot.0000000000000061] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW In liver transplantation, the ischemia/reperfusion injury (IRI) is influenced by factors related to graft quality, organ procurement and the transplant procedure itself. However, in brain-dead donors, the process of death itself also thoroughly affects organ damage through breakdown of the autonomous nervous system and subsequent massive cytokine release. This review highlights the actual knowledge on these proinflammatory effects of brain death on IRI in liver transplantation. RECENT FINDINGS Brain death affects IRI either through hemodynamical or molecular effects with proinflammatory activation. Immunological effects are mainly mediated through Kupffer cell activation, leading to TNF-α and TLR4 amplification. Proinflammatory cytokines such as interleukin (IL)-6, IL-10, TNF-β and MIP-1α are released, together with activation of the innate immune system via natural killer cells and natural killer T cells, which promote organ damage and activation of fibrosis. Preprocurement treatment regimens attempt to hamper inflammatory response by the application of methylprednisolone or thymoglobulin to the donor. Selective P-selectin antagonism resulted in improved function in marginal liver grafts. Inhaled nitric oxide was found to reduce apoptosis in liver grafts. Other medications like the immunosuppressant tacrolimus produced conflicting results regarding organ protection. Furthermore, improved organ storage after procurement - such as machine perfusion - can diminish effects of IRI in a clinical setting. SUMMARY Brain death plays a fundamental role in the regulation of molecular markers triggering inflammation and IRI-related tissue damage in liver transplants. Although several treatment options have reached clinical application, to date, the effects of brain death during donor conditioning and organ procurement remain relevant for organ function and survival.
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10
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Egea-Guerrero JJ, Murillo-Cabezas F, Gordillo-Escobar E, Rodríguez-Rodríguez A, Enamorado-Enamorado J, Revuelto-Rey J, Pacheco-Sánchez M, León-Justel A, Domínguez-Roldán JM, Vilches-Arenas A. S100B protein may detect brain death development after severe traumatic brain injury. J Neurotrauma 2013; 30:1762-9. [PMID: 23710646 PMCID: PMC3796324 DOI: 10.1089/neu.2012.2606] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Despite improvements in the process of organ donation and transplants, the number of organ donors is progressively declining in developed countries. Therefore, the early detection of patients at risk for brain death (BD) is a priority for transplant teams seeking more efficient identification of potential donors. In the extensive literature on S100B as a biomarker for traumatic brain injury (TBI), no evidence appears to exist on its prognostic capacity as a predictor of BD after severe TBI. The objective of this study is to assess the value of including acute S100B levels in standard clinical data as an early screening tool for BD after severe TBI. This prospective study included patients with severe TBI (Glasgow Coma Scale score [GCS] ≤ 8) admitted to our Neurocritical Care Unit over a 30 month period. We collected the following clinical variables: age, gender, GCS score, pupillary alterations at admission, hypotension and pre-hospital desaturation, CT scan results, isolated TBI or other related injuries, Injury Severity Score (ISS), serum S100B levels at admission and 24 h post-admission, and a final diagnosis regarding BD. Of the 140 patients studied, 11.4% developed BD and showed significantly higher S100B concentrations (p<0.001). Multivariate analysis showed that bilateral unresponsive mydriasis at admission and serum S100B at 24 h post-admission had odds ratios (ORs) of 21.35 (p=0.005) and 4.9 (p=0.010), respectively. The same analysis on patients with photomotor reflex in one pupil at admission left only the 24 h S100B sample in the model (OR=15.5; p=0.009). Receiver operating characteristics (ROC) curve analysis on this group showed the highest area under the curve (AUC) (0.86; p=0.001) for 24 h S100B determinations. The cut off was set at 0.372 μg/L (85.7% sensitivity, 79.3% specificity, positive predictive value [PPV]=18.7% and negative predictive value [NPV]=98.9%). This study shows that pupillary responsiveness at admission, as well as 24 h serum S100B levels, could serve as screening tools for the early detection of patients at risk for BD after severe TBI.
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Affiliation(s)
- Juan J. Egea-Guerrero
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Francisco Murillo-Cabezas
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Elena Gordillo-Escobar
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Ana Rodríguez-Rodríguez
- Department of Clinical Biochemistry, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Judy Enamorado-Enamorado
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Jaume Revuelto-Rey
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - María Pacheco-Sánchez
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Antonio León-Justel
- Department of Clinical Biochemistry, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Jose M. Domínguez-Roldán
- NeuroCritical Care Unit, Virgen del Rocío University Hospital, IBIS/CSIC/University of Seville, Seville, Spain
| | - Angel Vilches-Arenas
- Department of Preventive Medicine and Public Health, IBIS/CSIC/University of Seville, Seville, Spain
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11
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Cui CB, Gerber DA. Donor-associated malignancy in kidney transplant patients. J Clin Invest 2013; 123:3708-9. [PMID: 23979157 DOI: 10.1172/jci70438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Skin cancer cells with donor genotype have been identified in allogeneic transplant patients; however, the donor contribution to the recipient's epithelial malignancy remains to be established. In this issue of the JCI, Verneuil et al. provide the first evidence for donor contribution to the malignant epithelium of skin squamous cell carcinoma in a kidney transplant recipient. This case report may have important implications for cancer research and clinical care of long-surviving kidney transplant patients.
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Affiliation(s)
- Cai-Bin Cui
- Department of Surgery, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599, USA
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Verneuil L, Varna M, Ratajczak P, Leboeuf C, Plassa LF, Elbouchtaoui M, Schneider P, Sandid W, Lebbé C, Peraldi MN, Sigaux F, de Thé H, Janin A. Human skin carcinoma arising from kidney transplant-derived tumor cells. J Clin Invest 2013; 123:3797-801. [PMID: 23979160 DOI: 10.1172/jci66721] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 05/23/2013] [Indexed: 01/04/2023] Open
Abstract
Tumor cells with donor genotype have been identified in human skin cancer after allogeneic transplantation; however, the donor contribution to the malignant epithelium has not been established. Kidney transplant recipients have an increased risk of invasive skin squamous cell carcinoma (SCC), which is associated with accumulation of the tumor suppressor p53 and TP53 mutations. In 21 skin SCCs from kidney transplant recipients, we systematically assessed p53 expression and donor/recipient origin in laser-microdissected p53+ tumor cells. In one patient, molecular analyses demonstrated that skin tumor cells had the donor genotype and harbored a TP53 mutation in codon 175. In a kidney graft biopsy performed 7 years before the skin SCC diagnosis, we found p53+ cells in the renal tubules. We identified the same TP53 mutation in these p53+ epithelial cells from the kidney transplant. These findings provide evidence for a donor epithelial cell contribution to the malignant skin epithelium in the recipient in the setting of allogeneic kidney transplantation. This finding has theoretical implications for cancer initiation and progression and clinical implications in the context of prolonged immunosuppression and longer survival of kidney transplant patients.
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Renders L, Heemann U. Chronic renal allograft damage after transplantation: what are the reasons, what can we do? Curr Opin Organ Transplant 2012; 17:634-9. [PMID: 23080067 DOI: 10.1097/mot.0b013e32835a4bfa] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE OF REVIEW Chronic renal allograft damage is one of the main problems after kidney transplantation. This review enumerates causes, describes available therapeutic options, and discusses options of the future. RECENT FINDINGS Alloantigen-dependent and alloantigen-independent factors are responsible for allograft damage. Prevention of renal allograft damage starts with interventions that occur surrounding the explantation in cadaveric organs. These include the use of dopamine or machine perfusion systems.Followed by the critical phase of ischemia/reperfusion injury, the LCN2/lipocalin-2, HAVCR1, and p38 MAPK pathway are new players involved in that process. Innate immunity plays a part, too. Cold ischemia time is associated with genes of apoptosis. Nondonor-specific antibodies like antihuman leukocyte antibodies-Ia or angiotensin type 1 receptor may also play a role. Recent research indicates that genetic polymorphism like the Ficolin-2 Ala258Ser polymorphism and the mannose-binding lectin-2 polymorphism are involved in that process. New therapeutic options are rare and in the future. However, there is some evidence that drugs interfering with metalloproteinases, sexual hormones like dihydroandrosterone, and mesenchymal stem cell therapy may be of importance. SUMMARY Taken together, although the understanding of chronic rejection has improved, the available therapeutic options remain scarce.
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Affiliation(s)
- Lutz Renders
- Department of Nephrology, Technical University of Munic, Munic, Germany.
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