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Tian G, Song S, Zhi Y, Qiu W, Chen Y, Sun X, Huang H, Yu Y, Jiao W, Li M, Lv G. Alloreactive T cells temporarily increased in the peripheral blood of patients before liver allograft rejection. Liver Transpl 2024; 30:1250-1263. [PMID: 38900031 PMCID: PMC11548824 DOI: 10.1097/lvt.0000000000000425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024]
Abstract
T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T-cell clones in peripheral blood during a clinical T-cell-mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cell samples spanning from pre-LTx to 1 year after LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial peripheral blood mononuclear cell samples were collected from 96 nonrejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors, and they were longitudinally compared to nonrejected patients. Donor-reactive T-cell clone was identified and tracked by cross-matching with the mappable donor-reactive T-cell receptor repertoire of each donor-recipient pair in 9 rejectors and 5 nonrejectors. Before transplantation, the naive T-cell percentage and T-cell receptor repertoire diversity of rejectors was comparable to that of healthy control, but it was reduced in nonrejectors. After transplantation, the naïve T-cell percentages decreased, and T-cell receptor repertoires were skewed in rejectors; the phenomenon was not observed in nonrejectors. Alloreactive clones increased in proportion in the peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T-cell decline and memory T-cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre-LTx and post-LTx peripheral blood mononuclear cell samples revealed that the pretransplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases and may facilitate disease prediction and management.
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Chiang HJ, Chuang YH, Li CW, Lin CC, Eng HL, Chen CL, Cheng YF, Chou MC. Usefulness of Diffusion-Weighted Imaging in Evaluating Acute Cellular Rejection and Monitoring Treatment Response in Liver Transplant Recipients. Diagnostics (Basel) 2024; 14:807. [PMID: 38667453 PMCID: PMC11049147 DOI: 10.3390/diagnostics14080807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/29/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Acute cellular rejection (ACR) is a significant immune issue among recipients following liver transplantation. Although diffusion-weighted magnetic resonance imaging (DWI) is widely used for diagnosing liver disease, it has not yet been utilized for monitoring ACR in patients after liver transplantation. Therefore, the aim of this study was to evaluate the efficacy of DWI in monitoring treatment response among recipients with ACR. This study enrolled 25 recipients with highly suspected ACR rejection, and all subjects underwent both biochemistry and DWI scans before and after treatment. A pathological biopsy was performed 4 to 24 h after the first MRI examination to confirm ACR and degree of rejection. All patients were followed up and underwent a repeated MRI scan when their liver function returned to the normal range. After data acquisition, the DWI data were post-processed to obtain the apparent diffusion coefficient (ADC) map on a voxel-by-voxel basis. Five regions of interest were identified on the liver parenchyma to measure the mean ADC values from each patient. Finally, the mean ADC values and biochemical markers were statistically compared between ACR and non-ACR groups. A receiver operating characteristic (ROC) curve was constructed to evaluate the performance of the ADC and biochemical data in detecting ACR, and correlation analysis was used to understand the relationship between the ADC values, biochemical markers, and the degree of rejection. The histopathologic results revealed that 20 recipients had ACR, including 10 mild, 9 moderate, and 1 severe rejection. The results demonstrated that the ACR patients had significantly lower hepatic ADC values than those in patients without ACR. After treatment, the hepatic ADC values in ACR patients significantly increased to levels similar to those in non-ACR patients with treatment. The ROC analysis showed that the sensitivity and specificity for detecting ACR were 80% and 95%, respectively. Furthermore, the correlation analysis revealed that the mean ADC value and alanine aminotransferase level had strong and moderate negative correlation with the degree of rejection, respectively (r = -0.72 and -0.47). The ADC values were useful for detecting hepatic ACR and monitoring treatment response after immunosuppressive therapy.
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Affiliation(s)
- Hsien-Jen Chiang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (H.-J.C.); (Y.-H.C.)
- Department of Diagnostic Radiology, Kaohsiung Municipal Feng Shan Hospital—Under the Management of Chang Gung Medical Foundation, Kaohsiung 83062, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Hsuan Chuang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (H.-J.C.); (Y.-H.C.)
| | - Chun-Wei Li
- Department of Medical Imaging and Radiological Sciences, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Chih-Che Lin
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (C.-C.L.); (C.-L.C.)
- Department of Surgery, Kaohsiung Municipal Feng Shan Hospital—Under the Management of Chang Gung Medical Foundation, Kaohsiung 83062, Taiwan
| | - Hock-Liew Eng
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan;
| | - Chao-Long Chen
- Liver Transplantation Center, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (C.-C.L.); (C.-L.C.)
| | - Yu-Fan Cheng
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; (H.-J.C.); (Y.-H.C.)
| | - Ming-Chung Chou
- Department of Medical Imaging and Radiological Sciences, College of Health Science, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Center for Big Data Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
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Qazi Arisar FA, Varghese R, Chen S, Xu W, Selzner M, McGilvray I, Sayed B, Reichman T, Shwaartz C, Cattral M, Ghanekar A, Sapisochin G, Jaeckel E, Tsien C, Selzner N, Lilly L, Bhat M. Trajectories of patients relisted for liver transplantation. Ann Hepatol 2024; 29:101168. [PMID: 37858675 DOI: 10.1016/j.aohep.2023.101168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 09/01/2023] [Accepted: 09/12/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION AND OBJECTIVES Recurrent cirrhosis complicates 10-30% of Liver transplants (LT) and can lead to consideration for re-transplantation. We evaluated the trajectories of relisted versus primary listed patients on the waitlist using a competing risk framework. MATERIALS AND METHODS We retrospectively examined 1,912 patients listed for LT at our centre between from 2012 to 2020. Cox proportional hazard models were used to assess overall survival (OS) by listing type and competing risk analysis Fine-Gray models were used to assess cumulative incidence of transplant by listing type. RESULTS 1,731 patients were included (104 relisted). 44.2% of relisted patients received exception points vs. 19.8% of primary listed patients (p<0.001). Patients relisted without exceptions, representing those with graft cirrhosis, had the worst OS (HR: 4.17, 95%CI 2.63 - 6.67, p=<0.0001) and lowest instantaneous rate of transplant (HR: 0.56, 95%CI 0.38 - 0.83, p=0.006) than primary listed with exception points. On multivariate analysis listing type, height, bilirubin and INR were associated with cumulative incidence of transplant, while listing type, bilirubin, INR, sodium, creatinine were associated with OS. Within relisted patients, there was a trend towards higher mortality (HR: 1.79, 95%CI 0.91 - 3.52, p=0.08) and low transplant incidence (HR: 0.51, 95%CI 0.22 - 1.15, p=0.07) for graft cirrhosis vs other relisting indications. CONCLUSIONS Patients relisted for LT are carefully curated and comprise a minority of the waitlist population. Despite their younger age, they have worse liver/kidney function, poor waitlist survival, and decreased transplant incidence suggesting the need for early relisting, while considering standardized exception points.
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Affiliation(s)
- Fakhar Ali Qazi Arisar
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Rhea Varghese
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; McMaster University, Faculty of Health Sciences, 1280 Main St W, Hamilton, ON L8S 4L8, Hamilton, Canada
| | - Shiyi Chen
- University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada; Princess Margaret Cancer Centre, 620 University Ave, Toronto, ON M5G 2C1, Canada
| | - Wei Xu
- University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada; Princess Margaret Cancer Centre, 620 University Ave, Toronto, ON M5G 2C1, Canada; Dalla Lana School of Public Health, 155 College St Room 500, Toronto, M5T 3M7 Canada
| | - Markus Selzner
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Ian McGilvray
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Blayne Sayed
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Trevor Reichman
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Chaya Shwaartz
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Mark Cattral
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Anand Ghanekar
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Gonzalo Sapisochin
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Elmar Jaeckel
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Cynthia Tsien
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Nazia Selzner
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Leslie Lilly
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada
| | - Mamatha Bhat
- University Health Network, 585 University Avenue, Toronto, M5G 2N2, Canada; University of Toronto, 27 King's College Clr, Toronto, M5S 1A1, Canada; Toronto General Hospital Research Institute, 200 Elizabeth Street, Toronto, M5G 2C4, Canada.
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Gökgöz G, Tortumlu G, Akça Bayar S, Yilmaz G, Haberal M. Peripapillary Vascular Density Measurement in Pediatric Renal and Liver Transplant. EXP CLIN TRANSPLANT 2022; 20:96-101. [PMID: 35570610 DOI: 10.6002/ect.pediatricsymp2022.o32] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Noninvasive monitorization of retinal structures of the eye could be a predictor for systemic microvasculature dysfunction in transplant recipients. In this study, our purpose was to determine the optic disc and peripapillary microvascular changes in pediatric patients who had undergone liver or renal transplant surgery. MATERIALS AND METHODS The study was performed at Başkent University. The medical records were reviewed, and patients who had liver or renal transplant in the last 10 years and were between 4 and 18 years old were included in the study. The optic disc and peripapillary vascular density parameters were obtained by optical coherence tomography angiography (Avanti RTVue XR). The results were compared with the results from age-matched, sex-matched, and spherical equivalent-matched healthy subjects. RESULTS Our study included 32 eyes of 16 liver transplant patients, 20 eyes of 10 renal transplant patients, and 64 eyes of 32 healthy participants (control). Whole image peripapillary, inside disc, peripapillary, superior and inferior hemisphere, and superior, inferior, temporal, and nasal quadrant peripapillary vascular densities were evaluated. No statistically significant differences in any parameter were noted between the healthy control group and the patient groups (P > .05 for all parameters). CONCLUSIONS Peripapillary vascular density measurements were not affected in pediatric renal and liver transplant patients.
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Affiliation(s)
- Gülşah Gökgöz
- From the Department of Ophthalmology, Baskent University Faculty of Medicine, Ankara, Turkey
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Lan Q, Li Y, Robertson J, Jin R. Modeling of pre-transplantation liver viability with spatial-temporal smooth variable selection. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2021; 208:106264. [PMID: 34256248 DOI: 10.1016/j.cmpb.2021.106264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 06/28/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND AND OBJECTIVE Liver viability assessment plays a critical role in liver transplantation, and the accuracy of the assessment directly determines the success of the transplantation surgery and patient's outcomes. With various factors that affect liver viability, including pre-existing medical conditions of donors, the procurement process, and preservation conditions, liver viability assessment is typically subjective, invasive or inconsistent in results among different surgeons and pathologists. Motivated by these challenges, we aimed to create a non-invasive statistical model utilizing spatial-temporal infrared image (IR) data to predict the binary liver viability (acceptable/unacceptable) during the preservation. METHODS The spatial-temporal features of liver surface temperature, monitored by IR thermography, are significantly correlated with the liver viability. A spatial-temporal smooth variable selection (STSVS) method is proposed to define the smoothness of model parameters corresponding to different liver surface regions at different times. RESULTS A case study, using porcine livers, has been performed to validate the efficacy of the STSVS method. The comparison results show that STSVS has the better overall prediction performance compared to the past state-of-the-art predictive models, including generalized linear model (GLM), support vector machine (SVM), LASSO, and Fused LASSO. Moreover, the significant predictors identified by the STSVS method indicate the importance of edges of lobes in predicting liver viability during the pre-transplantation preservation. CONCLUSIONS The proposed method has the best performance in predicting liver viability. This 'real-time' prediction method may increase the utilization of donors' livers without damaging tissues and time-consuming, yet imprecise feature assessment.
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Affiliation(s)
- Qing Lan
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA.
| | - Yifu Li
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA
| | - John Robertson
- Department of Biomedical Engineering and Mechanics, Virginia Tech, VA 24061, USA
| | - Ran Jin
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA
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Park JY, Choi YJ, Ri HS, Lee JM, Son HJ, Lee YS, Ryu JH, Yang KH. Impact of age on the incidence of complications after liver transplantation: A single-center retrospective study. Braz J Anesthesiol 2021; 71:387-394. [PMID: 33762194 PMCID: PMC9373325 DOI: 10.1016/j.bjane.2021.02.040] [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: 03/08/2019] [Revised: 01/31/2021] [Accepted: 02/06/2021] [Indexed: 11/29/2022] Open
Abstract
Background and objective Advances in surgical technique, postoperative management, and immunosuppressive therapy have led to a steady increase in the number of patients undergoing organ transplantation. This study aimed to compare the incidence of postoperative complications between young and elderly patients undergoing liver transplantation (LT) at a single university hospital. Method The medical records of 253 patients who underwent LT between January 2010 and July 2017 were retrospectively reviewed. The patients were divided into two groups: those younger than 65 years (group Y, n = 231) and those older than 65 years (group O, n = 22). Data on patient demographics, perioperative management, and postoperative complications were collected. Results The patients’ baseline characteristics, including underlying diseases and the Model for End-Stage Liver Disease scores, were not different between groups. Preoperative laboratory findings were not significantly different between the two groups, except for hemoglobin level. The total amounts of infused fluid and packed red blood cells were higher in group O than in group Y. The postoperative plasma creatinine level was higher in group O than in group Y; however, the incidence of postoperative complications was not considerably different between the two groups. In addition, there was no difference in the survival rate after LT depending on age. Conclusion With the development of medical technology, LT in elderly patients is not an operation to be avoided, and the prognosis is expected to improve. Therefore, continuous efforts to understand the disease characteristics and physical differences in elderly patients who require LT are essential.
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Affiliation(s)
- Ju Yeon Park
- Daedong Hospital, Department of Anesthesiology and Pain Medicine, Busan, Republic of Korea; Pusan National University Yangsan Hospital, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Republic of Korea
| | - Yoon Ji Choi
- Korea University Ansan Hospital, Department of Anesthesia and Pain Medicine, Ansan, Korea.
| | - Hyun-Su Ri
- Pusan National University Yangsan Hospital, Department of Anesthesia and Pain Medicine, Yangsan, Republic of Korea
| | - Jung Min Lee
- Korea University Ansan Hospital, Department of Anesthesia and Pain Medicine, Ansan, Korea
| | - Hyo Jung Son
- National Police Hospital, Department of Anesthesiology and Pain Medicine, Seoul, Korea
| | - Yoon Sook Lee
- Korea University Ansan Hospital, Department of Anesthesia and Pain Medicine, Ansan, Korea
| | - Je Ho Ryu
- Pusan National University School of Medicine, Pusan National University Yangsan Hospital, Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Yangsan, Republic of Korea
| | - Kwang Ho Yang
- Pusan National University School of Medicine, Pusan National University Yangsan Hospital, Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Yangsan, Republic of Korea
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Hepatogenic Potential and Liver Regeneration Effect of Human Liver-derived Mesenchymal-Like Stem Cells. Cells 2020; 9:cells9061521. [PMID: 32580448 PMCID: PMC7348751 DOI: 10.3390/cells9061521] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/18/2020] [Accepted: 06/20/2020] [Indexed: 12/22/2022] Open
Abstract
Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers (GATA4 and FOXA1). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation (CPM and CD133) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (ALB, HNF4A, and AFP). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.
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Amiri M, Toosi MN, Moazzami B, Jafarian A, Shahsavari H, Javaherian M, Dashti H, Fakhar N, Karimi M, Khani F. Factors Associated With Length of Hospital Stay Following Liver Transplant Surgery. EXP CLIN TRANSPLANT 2020; 18:313-319. [PMID: 32133943 DOI: 10.6002/ect.2019.0077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Length of stay is considered an important surrogate for transplant survival rate and resource utilization. Therefore, in the present study, our aim was to determine factors affecting length of hospital stay. MATERIALS AND METHODS We retrospectively analyzed records of patients who underwent liver transplant at the Tehran University of Medical Sciences Liver Transplantation Center from March 2014 to March 2016. RESULTS For our final analyses, there were 161 adult recipients, including 106 males (65.8%) and 55 females (34.1%). Univariate analyses showed that body mass index, Modelfor End-Stage Liver Disease score, duration of surgery, number of administered packed red blood cells and fibrinogen during surgery, reoperation, retransplant, bacterial infection, pleural effusion, ascites, renal failure that required dialysis, and wound infection were risk factors for length of hospital stay. After multivariate linear regression analysis, only body mass index (β = 0.016; P = .028), Model for End-Stage Liver Disease score (β = 0.017; P = .002), surgical duration (β = 0.002; P = .001), reoperation (β = 0.016; P < .001), presence of pleural effusion (β = 0.212; P = .042), and management of bacterial infection (β = 0.21; P = .03) and psychiatric problems after liver transplant (β = 0.213; P = .025) were independent risk factors for length of hospital stay. CONCLUSIONS The present study showed that multiple preoperative, intraoperative, and postoperative variables could have an impact on length of hospitalization. Therefore, methods for assessing these factors could improve patient outcomes and resource savings in liver transplant centers.
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Affiliation(s)
- Mahmoud Amiri
- >From the Department of Medical-Surgical Nursing, School of Nursing and Midwifery, University of Medical Sciences, Tehran, Iran
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Gao Z, Du P, Jin R, Robertson JL. Surface temperature monitoring in liver procurement via functional variance change-point analysis. Ann Appl Stat 2020. [DOI: 10.1214/19-aoas1297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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10
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Hu C, Zhao L, Wu Z, Li L. Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury. Stem Cell Res Ther 2020; 11:88. [PMID: 32106875 PMCID: PMC7047366 DOI: 10.1186/s13287-020-01596-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/29/2020] [Accepted: 02/10/2020] [Indexed: 02/07/2023] Open
Abstract
Acetaminophen (APAP)-induced injury is a common clinical phenomenon that not only occurs in a dose-dependent manner but also occurs in some idiosyncratic individuals in a dose-independent manner. APAP overdose generally results in acute liver injury via the initiation of oxidative stress, endoplasmic reticulum (ER) stress, autophagy, liver inflammation, and microcirculatory dysfunction. Liver transplantation is the only effective strategy for treating APAP-induced liver failure, but liver transplantation is inhibited by scarce availability of donor liver grafts, acute graft rejection, lifelong immunosuppression, and unbearable costs. Currently, N-acetylcysteine (NAC) effectively restores liver functions early after APAP intake, but it does not protect against APAP-induced injury at the late stage. An increasing number of animal studies have demonstrated that mesenchymal stem cells (MSCs) significantly attenuate acute liver injury through their migratory capacity, hepatogenic differentiation, immunoregulatory capacity, and paracrine effects in acute liver failure (ALF). In this review, we comprehensively discuss the mechanisms of APAP overdose-induced liver injury and current therapies for treating APAP-induced liver injury. We then comprehensively summarize recent studies about transplantation of MSC and MSC derivatives for treating APAP-induced liver injury. We firmly believe that MSCs and their derivatives will effectively promote liver regeneration and liver injury repair in APAP overdose-treated animals and patients. To this end, MSC-based therapies may serve as an effective strategy for patients who are waiting for liver transplantation during the early and late stages of APAP-induced ALF in the near future.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lingfei Zhao
- Kidney Disease Center, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.,Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou, Zhejiang, People's Republic of China.,Institute of Nephrology, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhongwen Wu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. .,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.
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Sahinturk H, Ozdemirkan A, Zeyneloglu P, Gedik E, Pirat A, Haberal M. Early Postoperative Acute Kidney Injury Among Pediatric Liver Transplant Recipients. EXP CLIN TRANSPLANT 2019; 19:659-663. [PMID: 30880650 DOI: 10.6002/ect.2018.0214] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Acute kidney injury after pediatric liver transplant is associated with increased morbidity and mortality. Here, we evaluated children with acute kidney injury early posttransplant using KDIGO criteria to determine incidence, risk factors, and clinical outcomes. MATERIALS AND METHODS In this retrospective cohort study, medical records of all patients < 16 years old who underwent liver transplant from April 2007 to April 2017 were reviewed. RESULTS Of 117 study patients, 69 (59%) were male and median age at transplant was 72 months (range, 12-120 mo). Forty children (34.2%) had postoperative acute kidney injury, with most having stage 1 disease (n = 21). Compared with children who had acute kidney injury versus those who did not, preoperative activated partial thromboplastin time (median 35.6 s [interquartile range, 32.4-42.8 s] vs 42.5 s [interquartile range, 35-49 s]; P = .007), intraoperative lactate levels at end of surgery (median 5.3 mmol/L [interquartile range, 3.3-8.6 mmol/L] vs 7.9 mmol/L [interquartile range, 4.3-11.2 mmol/L]; P = .044), and need for open abdomen (3% vs 15%; P= .024) were significantly higher. Logistic regression analysis revealed that preoperative high activated partial thromboplastin time (P= .02), intraoperative lactate levels at end of surgery (P = .02), and need for open abdomen (P = .03) were independent risk factors for acute kidney injury. Children who developed acute kidney injury had significantly longer intensive care unit stay (7.1 ± 8.5 vs 4.4 ± 5.4 days, P= .04) and mortality (12.8% vs 1.8%; P = .01). CONCLUSIONS Early postoperative acute kidney injury occurred in 34.2% of pediatric liver transplant recipients, with patients having increased mortality risk. High preoperative activated partial throm-boplastin time, high intraoperative end of surgery lactate levels, and need for open abdomen were shown to be associated with acute kidney injury after pediatric liver transplant.
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Affiliation(s)
- Helin Sahinturk
- From the Anesthesiology and ICM Department, Baskent University Faculty of Medicine, Ankara, Turkey
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12
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Pérez Civantos D, Muñoz Cantero A, Robles Marcos M, Fuentes Morillas F, Cerezo Arias M, Fariñas Seijas H. Utility of Basal Regional Oximetry as an Early Predictor of Graft Failure After Liver Transplant. Transplant Proc 2019; 51:353-358. [PMID: 30879540 DOI: 10.1016/j.transproceed.2018.10.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 10/23/2018] [Indexed: 11/25/2022]
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13
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Liver Regeneration after Acetaminophen Hepatotoxicity: Mechanisms and Therapeutic Opportunities. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:719-729. [PMID: 30653954 DOI: 10.1016/j.ajpath.2018.12.006] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/11/2018] [Accepted: 12/17/2018] [Indexed: 12/26/2022]
Abstract
Acetaminophen (N-acetyl-para-aminophenol; APAP) overdose is the most common cause of acute liver failure in the Western world, with limited treatment opportunities. For years, research on APAP overdose has been focused on investigating the mechanisms of hepatotoxicity, with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a crucial determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose dependent and impaired after severe APAP overdose. Although robust regenerative response is associated with spontaneous recovery and survival, impaired regeneration results in faster progression of injury and death after APAP overdose. APAP hepatotoxicity-induced liver regeneration involves a complex time- and dose-dependent interplay of several signaling mediators, including growth factors, cytokines, angiogenic factors, and other mitogenic pathways. Compared with the liver injury, which is established before most patients seek medical attention and has proved difficult to manipulate, liver regeneration can be potentially modulated even in late-stage APAP-induced acute liver failure. Despite recent efforts to study the mechanisms of liver regeneration after APAP-induced liver injury, more comprehensive research in this area is required, especially regarding factors that contribute to impaired regenerative response, to develop novel regenerative therapies for APAP-induced acute liver failure.
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14
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Lin CC, Ou HY, Chuang YH, Chiang HJ, Yu CC, Lazo M, Tsang LLC, Huang TL, Lin CC, Chen CL, Cheng YF. Diffusion-Weighted Magnetic Resonance Imaging in Liver Graft Rejection. Transplant Proc 2018; 50:2675-2678. [PMID: 30401375 DOI: 10.1016/j.transproceed.2018.04.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 03/22/2018] [Accepted: 04/06/2018] [Indexed: 01/24/2023]
Abstract
OBJECTIVE The purpose of this study is to evaluate the use of diffusion-weighted magnetic resonance imaging (DWMRI) in the assessment of graft rejection after liver transplantation (LT). METHODS From June 2017 to January 2018, 32 patients were included in the study with a mean age of 52.3 years. All patients underwent LT. The DWMRI was performed using the apparent diffusion coefficient map and measuring the different b-values (b-400, b-600, b-800, and b-1000). These measurements were compared with the histopathology results. Statistical analysis included t test, analysis of variance, and area under the curve for receiver operating characteristic (ROC). RESULTS There were 17 patients without rejection and 15 patients with liver graft rejection diagnosed by histopathology. The mean (SD) results between the nonrejection and rejection groups were as follows: b-400 = 1.568 (0.265) vs 1.519 (0.119) (P = .089), b-600 = 1.380 (0.181) vs 1.284 (0.106) (P = .039), b-800 = 1.262 (0.170) vs 1.170 (0.086) (P = .035), b-1000 = 1.109 (0.129) vs 1.098 (0.078) (P = .095); B-values × 10-3 mm2/s. Only b-600 (P = .04) and b-800 (P = .04) values have significant differences between the 2 groups. B-600 showed 90.48% sensitivity and 83.33% specificity (ROC area under the curve = 0.784; P < .001), and b-800 showed 90.38% sensitivity and 83.03% specificity (ROC area under the curve = 0.816; P < .001). The values obtained with the apparent diffusion coefficient in b-800 were clearly differentiated between the mild, moderate, and severe degrees of rejection (P < .001). CONCLUSION Measurement of b-600 and b-800 values using DWMRI may be used for the diagnosis of graft rejection after LT.
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Affiliation(s)
- C-C Lin
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - H-Y Ou
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Y-H Chuang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - H-J Chiang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-C Yu
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - M Lazo
- Department of Diagnostic Radiology, St. Luke's Medical Center-Global City, Metro Malila, Philippines
| | - L L-C Tsang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - T-L Huang
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-C Lin
- Liver Transplantation Program and Departments of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - C-L Chen
- Liver Transplantation Program and Departments of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Y-F Cheng
- Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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15
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Yang G, Ou M, Chen H, Guo C, Chen J, Lin H, Tang D, Xue W, Li W, Sui W, Dai Y. Characteristic analysis of TCR β-chain CDR3 repertoire for pre- and post-liver transplantation. Oncotarget 2018; 9:34506-34519. [PMID: 30349645 PMCID: PMC6195376 DOI: 10.18632/oncotarget.26138] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 09/10/2018] [Indexed: 12/20/2022] Open
Abstract
Liver cirrhosis of hepatitis B is an immune-related disease in which liver cells die during the body’s immune system activation to clear the virus, and the progress is closely related to T lymphocytes. T lymphocyte cells recognise antigens, specifically by major histocompatibility complex (MHC), through a membrane protein T cell receptor (TCR). Here, we used high throughput immune repertoire sequencing technique to study the characteristics and diversity of the TCR repertoire between patients who underwent liver transplantation and healthy controls (NC). We sequenced the TCR β-chain complementary-determining region 3 (CDR3) repertoire in peripheral blood mononuclear cells (PBMCs) from 6 liver transplantation patients before transplantation (Pre) and on the first (Post1) and seventh days (Post7) after transplantation along with 6 NC. We observed that the distributions of CDR3, VD indel, and DJ indel lengths were similar among the Pre, Post1, Post7 and NC groups. We found that the TCR repertoire diversity of transplantation groups was relatively lower compared to NC group. The Pre-group had more highly expanded T cell clones compared to Post1, Post7 and NC groups, and the diversity of the T cell repertoire of the Post7 group was significantly decreased compared to the Pre, Post1 and NC groups. In addition, we found our results also show that various TRBV expression increased and some public sequences at different time points after liver transplantation, and the expression levels of 3 TRBV segments and 2 TRBJ segments were also significantly different in Pre, Post1, Post7 and NC groups. Moreover, 1 aa sequence shared by all liver transplantation patients and 2 aa sequences shared by at least two groups, which may serve as biomarkers to monitor the immune status of liver transplant patients.
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Affiliation(s)
- Guiqi Yang
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China
| | - Minglin Ou
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China.,Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Huaizhou Chen
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China
| | - Changchun Guo
- The Pingshan People's Hospital of Shenzhen, Shenzhen, Guangdong 518118, P.R. China
| | - Jiejing Chen
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China
| | - Hua Lin
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China
| | - Donge Tang
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R. China
| | - Wen Xue
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China
| | - Wenlong Li
- The Technology Company of iCarbonX, Shenzhen, Guangdong 518000, P.R. China
| | - Weiguo Sui
- Guangxi Key Laboratory of Metabolic Diseases Research, Guilin 541002, P.R. China
| | - Yong Dai
- Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, Shenzhen, Guangdong 518020, P.R. China
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16
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Lan Q, Sun H, Robertson J, Deng X, Jin R. Non-invasive assessment of liver quality in transplantation based on thermal imaging analysis. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2018; 164:31-47. [PMID: 30195430 DOI: 10.1016/j.cmpb.2018.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Revised: 05/25/2018] [Accepted: 06/05/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND AND OBJECTIVE Liver quality evaluation is one of the vital steps for predicting the success of liver transplantation. Current evaluation methods, such as biopsy and visual inspection, which are either invasive or lack of consistent standards, provide limited predictive value of long-term transplant viability. Objective analytical models, based on the real-time infrared images of livers during perfusion and preservation, are proposed as novel methods to precisely evaluate donated liver quality. METHODS In this study, by using principal component analysis to extract infrared image features as predictors, we construct a multivariate logistic regression model for single liver quality evaluation, and a multi-task learning logistic regression model for cross-liver quality evaluation. RESULTS The single liver quality predictions show testing errors of 0%. The leave-one-liver-out predictions show testing errors ranging from 9% to 36%. CONCLUSIONS It is found that there is a strong correlation between the viability of livers and the infrared image features in both single liver and cross-liver quality evaluations. These analytical methods also determine that the selected significant infrared image features indicate regional difference in viability and show that more stringent pre-implantation evaluation may be needed to predict transplant outcomes.
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Affiliation(s)
- Qing Lan
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA
| | - Hongyue Sun
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA
| | - John Robertson
- School of Biomedical Engineering and Sciences, Virginia Tech, VA 24061, USA
| | - Xinwei Deng
- Department of Statistics, Virginia Tech, VA 24061, USA
| | - Ran Jin
- Grado Department of Industrial and Systems Engineering, Virginia Tech, Blacksburg, VA 24061, USA.
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17
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The multiple functions of melatonin in regenerative medicine. Ageing Res Rev 2018; 45:33-52. [PMID: 29630951 DOI: 10.1016/j.arr.2018.04.003] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 04/03/2018] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
Melatonin research has been experiencing hyper growth in the last two decades; this relates to its numerous physiological functions including anti-inflammation, oncostasis, circadian and endocrine rhythm regulation, and its potent antioxidant activity. Recently, a large number of studies have focused on the role of melatonin in the regeneration of cells or tissues after their partial loss. In this review, we discuss the recent findings on the molecular involvement of melatonin in the regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others.
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18
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Sambathkumar R, Akkerman R, Dastidar S, Roelandt P, Kumar M, Bajaj M, Mestre Rosa AR, Helsen N, Vanslembrouck V, Kalo E, Khurana S, Laureys J, Gysemans C, Faas MM, de Vos P, Verfaillie CM. Generation of hepatocyte- and endocrine pancreatic-like cells from human induced endodermal progenitor cells. PLoS One 2018; 13:e0197046. [PMID: 29750821 PMCID: PMC5947914 DOI: 10.1371/journal.pone.0197046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2017] [Accepted: 04/25/2018] [Indexed: 01/27/2023] Open
Abstract
Multipotent Adult Progenitor Cells (MAPCs) are one potential stem cell source to generate functional hepatocytes or β-cells. However, human MAPCs have less plasticity than pluripotent stem cells (PSCs), as their ability to generate endodermal cells is not robust. Here we studied the role of 14 transcription factors (TFs) in reprogramming MAPCs to induced endodermal progenitor cells (iENDO cells), defined as cells that can be long-term expanded and differentiated to both hepatocyte- and endocrine pancreatic-like cells. We demonstrated that 14 TF-iENDO cells can be expanded for at least 20 passages, differentiate spontaneously to hepatocyte-, endocrine pancreatic-, gut tube-like cells as well as endodermal tumor formation when grafted in immunodeficient mice. Furthermore, iENDO cells can be differentiated in vitro into hepatocyte- and endocrine pancreatic-like cells. However, the pluripotency TF OCT4, which is not silenced in iENDO cells, may contribute to the incomplete differentiation to mature cells in vitro and to endodermal tumor formation in vivo. Nevertheless, the studies presented here provide evidence that reprogramming of adult stem cells to an endodermal intermediate progenitor, which can be expanded and differentiate to multiple endodermal cell types, might be a valid alternative for the use of PSCs for creation of endodermal cell types.
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Affiliation(s)
- Rangarajan Sambathkumar
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
- * E-mail: (CMV); (RS)
| | - Renate Akkerman
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
- University of Groningen, University Medical Center Groningen (UMCG), Pathology and Medical Biology, Division of Medical Biology, Section Immunoendocrinology, Groningen, The Netherlands
| | - Sumitava Dastidar
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Philip Roelandt
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Manoj Kumar
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Manmohan Bajaj
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Ana Rita Mestre Rosa
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Nicky Helsen
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Veerle Vanslembrouck
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Eric Kalo
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
| | - Satish Khurana
- School of Biology, Indian Institute of Science Education and Research, Thiruvananthapuram, Kerala, India
| | - Jos Laureys
- KU Leuven, Department of Clinical and Experimental Medicine, Clinical and Experimental Endocrinology unit, Leuven, Belgium
| | - Conny Gysemans
- KU Leuven, Department of Clinical and Experimental Medicine, Clinical and Experimental Endocrinology unit, Leuven, Belgium
| | - Marijke M. Faas
- University of Groningen, University Medical Center Groningen (UMCG), Pathology and Medical Biology, Division of Medical Biology, Section Immunoendocrinology, Groningen, The Netherlands
- University of Groningen, University Medical Center Groningen (UMCG), Department of Obstetrics and Gynecology, Groningen, The Netherlands
| | - Paul de Vos
- University of Groningen, University Medical Center Groningen (UMCG), Pathology and Medical Biology, Division of Medical Biology, Section Immunoendocrinology, Groningen, The Netherlands
| | - Catherine M. Verfaillie
- KU Leuven, Interdepartmental Stem Cell Institute, Department of Development and Regeneration, Stem Cell Biology and Embryology, Leuven, Belgium
- * E-mail: (CMV); (RS)
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Patel P, Okoronkwo N, Pyrsopoulos NT. Future Approaches and Therapeutic Modalities for Acute Liver Failure. Clin Liver Dis 2018; 22:419-427. [PMID: 29605076 DOI: 10.1016/j.cld.2018.01.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The current gold standard for the management of acute liver failure is liver transplantation. However, because of organ shortages, other modalities of therapy are necessary as a possible bridge. This article discusses the current modalities as well as the future management of acute liver failure. Liver assist devices, hepatocyte transplantation, stem cell transplant, organogenesis, and repopulation of decellularized organs are discussed.
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Affiliation(s)
- Pavan Patel
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
| | - Nneoma Okoronkwo
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA
| | - Nikolaos T Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB H-538, Newark, NJ 07103, USA.
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20
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Wang X, Young DJ, Wu YL, Loh XJ. Thermogelling 3D Systems towards Stem Cell-Based Tissue Regeneration Therapies. Molecules 2018; 23:E553. [PMID: 29498651 PMCID: PMC6017244 DOI: 10.3390/molecules23030553] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 02/25/2018] [Accepted: 02/26/2018] [Indexed: 02/08/2023] Open
Abstract
Stem cell culturing and differentiation is a very important research direction for tissue engineering. Thermogels are well suited for encapsulating cells because of their non-biotoxic nature and mild sol-gel transition as temperature increases. In particular, thermogels provide a 3D growth environment for stem cell growth, which is more similar to the extracellular matrix than flat substrates, so thermogels as a medium can overcome many of the cell abnormalities caused by 2D cell growth. In this review, we summarize the applications of thermogels in cell and stem cell culture in recent years. We also elaborate on the methods to induce stem cell differentiation by using thermogel-based 3D scaffolds. In particular, thermogels, encapsulating specific differentiation-inducing factor and having specific structures and moduli, can induce the differentiation into the desired tissue cells. Three dimensional thermogel scaffolds that control the growth and differentiation of cells will undoubtedly have a bright future in regenerative medicine.
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Affiliation(s)
- Xiaoyuan Wang
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
| | - David James Young
- Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore 4558, Queensland, Australia.
| | - Yun-Long Wu
- Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
| | - Xian Jun Loh
- A*STAR (Agency for Science, Technology and Research), Institute of Materials Science and Engineering, 2 Fusionopolis Way, Innovis, #08-03, Singapore 138634, Singapore.
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Kim Y, Kang K, Yoon S, Kim JS, Park SA, Kim WD, Lee SB, Ryu KY, Jeong J, Choi D. Prolongation of liver-specific function for primary hepatocytes maintenance in 3D printed architectures. Organogenesis 2018; 14:1-12. [PMID: 29359998 DOI: 10.1080/15476278.2018.1423931] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Isolated primary hepatocytes from the liver are very similar to in vivo native liver hepatocytes, but they have the disadvantage of a limited lifespan in 2D culture. Although a sandwich culture and 3D organoids with mesenchymal stem cells (MSCs) as an attractive assistant cell source to extend lifespan can be used, it cannot fully reproduce the in vivo architecture. Moreover, long-term 3D culture leads to cell death because of hypoxic stress. Therefore, to overcome the drawback of 2D and 3D organoids, we try to use a 3D printing technique using alginate hydrogels with primary hepatocytes and MSCs. The viability of isolated hepatocytes was more than 90%, and the cells remained alive for 7 days without morphological changes in the 3D hepatic architecture with MSCs. Compared to a 2D system, the expression level of functional hepatic genes and proteins was higher for up to 7 days in the 3D hepatic architecture. These results suggest that both the 3D bio-printing technique and paracrine molecules secreted by MSCs supported long-term culture of hepatocytes without morphological changes. Thus, this technique allows for widespread expansion of cells while forming multicellular aggregates, may be applied to drug screening and could be an efficient method for developing an artificial liver.
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Affiliation(s)
- Yohan Kim
- a Department of Translational Medicine , Graduate School of Biomedical Science and Engineering, Hanyang University , Seoul , Republic of Korea.,b HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University , Seoul , Republic of Korea.,c Department of Surgery , Hanyang University College of Medicine , Seoul , Republic of Korea
| | - Kyojin Kang
- a Department of Translational Medicine , Graduate School of Biomedical Science and Engineering, Hanyang University , Seoul , Republic of Korea.,b HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University , Seoul , Republic of Korea.,c Department of Surgery , Hanyang University College of Medicine , Seoul , Republic of Korea
| | - Sangtae Yoon
- a Department of Translational Medicine , Graduate School of Biomedical Science and Engineering, Hanyang University , Seoul , Republic of Korea.,b HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University , Seoul , Republic of Korea.,c Department of Surgery , Hanyang University College of Medicine , Seoul , Republic of Korea
| | - Ji Sook Kim
- d Department of Pathology , Hanyang University College of Medicine , Seoul , Republic of Korea
| | - Su A Park
- e Department of Nature-Inspired Nanoconvergence Systems , Korea Institute of Machinery and Materials , Daejeon , Republic of Korea
| | - Wan Doo Kim
- e Department of Nature-Inspired Nanoconvergence Systems , Korea Institute of Machinery and Materials , Daejeon , Republic of Korea
| | - Seung Bum Lee
- f Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological & Medical Science (KIRAMS) , Seoul , Republic of Korea
| | - Ki-Young Ryu
- g Department of Obstetrics and Gynecology, Hanyang University College of Medicine , Seoul , Korea
| | - Jaemin Jeong
- b HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University , Seoul , Republic of Korea.,c Department of Surgery , Hanyang University College of Medicine , Seoul , Republic of Korea
| | - Dongho Choi
- a Department of Translational Medicine , Graduate School of Biomedical Science and Engineering, Hanyang University , Seoul , Republic of Korea.,b HY Indang Center of Regenerative Medicine and Stem Cell Research, Hanyang University , Seoul , Republic of Korea.,c Department of Surgery , Hanyang University College of Medicine , Seoul , Republic of Korea
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Wang YJ, He NH, Wang ZW, Niu RZ, Liu J, Wen HW, Li JJ, Li MD, Wang YM. Assessment of the Combined Effect of Plasma Exchange and Plasma Perfusion on Patients with Severe Hepatitis Awaiting Orthotopic Liver Transplantation. Int J Artif Organs 2018; 27:40-4. [PMID: 14986595 DOI: 10.1177/039139880402700109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
To determine if plasma exchange combined with plasma perfusion is a reliable and effective temporary liver support treatment for patients on the waiting list for OLT, we tested this method in 5 patients with end-stage and 3 patients with middle-stage severe hepatitis. Four patients were successfully controlled until a donor liver was available 4 to 13 days later. In contrast, the remaining 4 patients were not adequately controlled by this treatment and experienced aggravated disease progression, dying 3 to 8 days after treatment while still awaiting OLT. Of those 4 patients who received OLT, 2 patients died from multi-organ failure caused by hepatic failure, while the other 2 survived. These findings show that plasma exchange combined with plasma perfusion provides temporary support for some patients on the waiting list for OLT. The ability of patients to successfully bridge to OLT is closely associated with the degree of liver failure, complications, multi-organ failure, and the length of the waiting period for a donor liver.
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Affiliation(s)
- Y J Wang
- Institute of Infectious Diseases, Artificial Liver Unit, Southwest Hospital, Third Military Medical University, Chongqing, China.
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Wehbe TW, Abi Chahine NH, Annous ARA, Ferri MA, Boulous RC, El-Mestrah MF. A case report of congenital glycogen storage liver cirrhosis treated with bone marrow derived stem cells. Stem Cell Investig 2017; 4:73. [PMID: 29057245 DOI: 10.21037/sci.2017.07.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 07/13/2017] [Indexed: 11/06/2022]
Abstract
Liver cirrhosis represents a state of end-stage failure that is usually fatal. The condition results in liver dysfunction, recurrent ascites, encephalopathy, renal failure, splenomegaly, bleeding, and a poor quality of life in general. With the current severe shortage of donated organs, the only available treatment in the developing countries remains palliative care. We report a case of congenital metabolic liver cirrhosis due to glycogen storage disease diagnosed at age eight. The patient, a male, received bone marrow derived mononuclear cells (BMMC) at age 16 and again at age 17 with significant improvement of his biochemical liver function tests, ascites build-up, asthenia, splenomegaly and quality of life. Furthermore, liver biopsies showed clear reduction of the inflammation and fibrosis from Ishak score dropped from 3 to 1 paralleling the symptomatic improvement of the patient.
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Affiliation(s)
- Terek W Wehbe
- Department of Hematology, The Notre Dame University Hospital, Jounieh, Lebanon
| | | | - Abdul-Rahman A Annous
- Hanan Lebanese-French Laboratory for Pathology, University of Balamand and Open Arab University, Balamand Al Kurah, Lebanon
| | - Mohammad A Ferri
- Al-Salam Hospital, Department of Gastroenterology, Tripoli, Lebanon
| | - Robert C Boulous
- Department of Pathology, The Notre Dame University Hospital, Beirut, Lebanon
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Krespi MR, Tankurt A, Acarli K, Kanmaz T, Yankol Y, Kalayoglu M. Beliefs of Living Donors About Recipients' End-Stage Liver Failure and Surgery for Organ Donation. Transplant Proc 2017; 49:1369-1375. [PMID: 28736009 DOI: 10.1016/j.transproceed.2017.02.050] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 01/26/2017] [Accepted: 02/07/2017] [Indexed: 11/29/2022]
Abstract
BACKGROUND The concept of beliefs could provide a basis for how donors may perceive recipients' end-stage liver failure (ESLF) and surgery for organ donation. However, there is no such quantitative study. Therefore, the objective of this study was to explore beliefs of living donors about recipients' ESLF and surgery for organ donation. METHODS The sample comprised 16 living donors who donated a part of their liver to a patient who had ESLF. The data were analyzed by following established procedures for inductive qualitative analysis. RESULTS Analysis showed that donors' beliefs can be viewed in a number of groups. Beliefs about recipients' ESLF included diverse explanations for ESLF (blaming oneself and physicians) and physical symptoms (developmental slowing down). Beliefs about being a donor included reasons for being a donor (performing a good deed, being healed), barriers to being a donor (other people being ignorant and selfish), ways to manage these barriers (following one's gut feeling), and factors facilitating being a donor (the feeling that one does not have many people to leave behind). Beliefs about surgery for organ donation included physical effects (pain, feeling stiff). Beliefs about organ donation included views that general organ donation should be encouraged and that people's awareness should be raised. CONCLUSIONS Existing psychological perspectives could help to interpret some beliefs. Nevertheless, other beliefs, not previously reported, could be considered as targets for individual consultations/psycho-educational programs for fostering emotional well-being.
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Affiliation(s)
- M R Krespi
- Department of Psychology, Kadir Has University, Istanbul, Turkey.
| | - A Tankurt
- Department of Child and Adolescent Mental Health, Bezmialem Foundation Trust University, Istanbul, Turkey
| | - K Acarli
- Memorial Sisli Hospital, Centre of Organ Transplantation, Istanbul, Turkey
| | - T Kanmaz
- Memorial Sisli Hospital, Centre of Organ Transplantation, Istanbul, Turkey
| | - Y Yankol
- Memorial Sisli Hospital, Centre of Organ Transplantation, Istanbul, Turkey
| | - M Kalayoglu
- Memorial Sisli Hospital, Centre of Organ Transplantation, Istanbul, Turkey
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25
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Hong JH, Lee HJ, Jeong B. Injectable Polypeptide Thermogel as a Tissue Engineering System for Hepatogenic Differentiation of Tonsil-Derived Mesenchymal Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2017; 9:11568-11576. [PMID: 28290667 DOI: 10.1021/acsami.7b02488] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
A poly(ethylene glycol)-b-poly(l-alanine) (PEG-l-PA) hydrogel incorporating tonsil-derived mesenchymal stem cells (TMSCs), tauroursodeoxycholic acid (TUDCA), hepatocyte growth factor (HGF), and fibroblast growth factor 4 (FGF4) was prepared through thermal gelation of an aqueous polymer solution for an injectable tissue engineering application. The thermal gelation accompanied conformational changes of both PA and PEG blocks. The gel modulus at 37 °C was controlled to be 1000 Pa by using a 14.0 wt % aqueous polymer solution. The gel preserved its physical integrity during the 3D culture of the cells. TUDCA, HGF, and FGF4 were released from the PEG-l-PA hydrogel over 21 days of the 3D cell culture period. TMSCs initially exhibited a spherical shape, whereas some fibers protruded from the cells on days 14-21 of 3D culture. The injectable system exhibited pronounced expressions of the hepatic biomarkers at both mRNA and protein levels, which are significantly better than the commercially available hyaluronic acid gel. In particular, the hepatogenically differentiated cells from the TMSCs in the injectable system demonstrated hepatic biofunctions comparable to HepG2 cells for the uptakes of low density lipoproteins (52%) and indocyanine green (76%), and the production of albumin (40%) and urea (52%), which are also significantly better than the 3D-cultured cells in the commercially available hyaluronic acid gel. Our studies suggest that the PEG-l-PA thermogel incorporating TMSCs, TUDCA, and growth factors is highly promising as an in situ forming tissue engineering system.
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Affiliation(s)
- Ja Hye Hong
- Department of Chemistry and Nanoscience, Ewha Womans University , 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea
| | - Hyun Jung Lee
- Department of Chemistry and Nanoscience, Ewha Womans University , 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea
| | - Byeongmoon Jeong
- Department of Chemistry and Nanoscience, Ewha Womans University , 52 Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea
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26
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Wei Q, Gao F, Zhuang R, Ling Q, Ke Q, Wu J, Shen T, Zhang M, Zhang M, Xu X, Zheng S. A national report from China Liver Transplant Registry: steroid avoidance after liver transplantation for hepatocellular carcinoma. Chin J Cancer Res 2017; 29:426-437. [PMID: 29142462 DOI: 10.21147/j.issn.1000-9604.2017.05.07] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Objective We aimed to evaluate the efficacy and safety of steroid-free immunosuppression after liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods We retrospectively analyzed HCC recipients without steroids after LT (SF group, n=368) based on the China Liver Transplant Registry (CLTR) database. These recipients were matched 1:2 with patients using steroids (S group, n=736) for the same period after LT for HCC, according to propensity scores. Results Multivariate analysis indicates that recipients with younger age [odds ratio (OR), 1.053; P=0.011], preoperative hepatitis B virus (HBV) DNA ≥1,000 copies/mL (OR, 2.597; P=0.004) and beyond Milan criteria (OR, 4.255; P<0.001) were identified as the risk factors associated with tumor recurrence in steroid avoidance recipients after LT. The patients fulfilling the Milan criteria in the SF group presented higher overall and tumor-free survival rates than those in the S group (P<0.05). Multivariate analysis revealed that recipient beyond Milan criteria was an independent prognostic factor for overall survival (OR, 1.690; P<0.001) and tumor-free survival (OR, 2.066; P<0.001). The incidences of new-onset diabetes mellitus (21.20%vs. 33.29%, P<0.001), new-onset hypertension (10.05%vs. 18.61%, P<0.001) and hyperlipidemia (4.08%vs. 7.20%, P=0.042) were significantly lower in the SF group. Conclusions Steroid-free immunosuppression could be safe and feasible for HBV-related HCC patients in LT. Age, HBV DNA level and Milan criteria maybe risk factors associated with tumor recurrence in steroid avoidance recipients. Recipient beyond Milan criteria was an independent prognostic factor and recipient fulfilling Milan criteria can benefit the most from steroid-free immunosuppression.
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Affiliation(s)
- Qiang Wei
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Feng Gao
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Runzhou Zhuang
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qi Ling
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qinghong Ke
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jian Wu
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Tian Shen
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Mangli Zhang
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Min Zhang
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xiao Xu
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
| | - Shusen Zheng
- Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.,Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou 310003, China
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27
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Krespi MR, Tankurt A, Acarlı K, Yankol Y, Kalayoglu M, Kanmaz T. Post-donation evaluation of life of donors of liver transplantation. COGENT PSYCHOLOGY 2016; 3:1262724. [DOI: 10.1080/23311908.2016.1262724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 11/16/2016] [Indexed: 10/20/2022] Open
Affiliation(s)
| | - Asli Tankurt
- Doga College, Counselling Service, Istanbul, Turkey
| | - Koray Acarlı
- Centre of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
| | - Yucel Yankol
- Centre of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
| | - Munci Kalayoglu
- Centre of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
| | - Turan Kanmaz
- Centre of Organ Transplantation, Memorial Sisli Hospital, Istanbul, Turkey
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28
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Identification of Novel and Noninvasive Biomarkers of Acute Cellular Rejection After Liver Transplantation by Protein Microarray. Transplant Direct 2016; 2:e118. [PMID: 27990483 PMCID: PMC5142373 DOI: 10.1097/txd.0000000000000630] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 09/13/2016] [Indexed: 12/20/2022] Open
Abstract
Background Acute cellular rejection (ACR) is one of the main factors in transplanted organ failure in liver transplantation. A precise marker for diagnosing or predicting rejection is not currently available; therefore, invasive liver biopsy is standard procedure. To develop a noninvasive method for precise diagnosis of ACR, we evaluated autoantibodies from patient sera as potential biomarkers using protein microarrays (seromics). Methods Sera from hepatitis C virus–positive ACR patients were compared to three hepatitis C virus cirrhosis control groups and healthy volunteers. The control groups consisted of 2 no-ACR groups obtained on postoperative day 28 and 1 year after transplantation and a preoperative group obtained 1 day before transplantation. For validation, we evaluated whether the candidate antibodies can distinguish ACR from other types of liver dysfunction after liver transplantation using enzyme-linked immunosorbent assay. Results Seromic analysis by weighted average difference (WAD) ranking and Mann-Whitney U test revealed a significant increase of 57 autoantibodies in the sera of ACR patients with liver dysfunction. Among the 57 candidates, autoantibodies to charged multivesicular body protein 2B, potassium channel tetramerization domain containing 14, voltage gated subfamily A regulatory beta subunit 3, and triosephosphate isomerase 1 were regarded as potential biomarkers of ACR after liver transplantation. Using 20 ACR patients with variable backgrounds for validation, the autoantibodies to charged multivesicular body protein 2B and triosephosphate isomerase 1 were significantly increased in ACR patients compared to other control groups. Conclusions A panel of autoantibodies identified by seromics as potential noninvasive biomarkers was clinically useful for diagnosing ACR after liver transplantation.
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29
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Johnson PN, Romanelli F, Smith KM, Ranjan D, Butler JS, Clifford TM. Analysis of Morbidity in Liver Transplant Recipients following Human Albumin Supplementation: A Retrospective Pilot Study. Prog Transplant 2016; 16:197-205. [PMID: 17007153 DOI: 10.1177/152692480601600303] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Objectives To assess incidence of morbidity (ie, documented infection, acute renal failure, acute graft rejection, acute cardiovascular events, and hospital read-mission rates) 6 months following liver transplantation using linear regression as a function of cumulative albumin dose. Design Retrospective chart review. Setting A 473-bed tertiary care teaching facility with a solid-organ transplantation center. Patients Forty liver transplant recipients examined from January 1 to December 31, 2003. Measurements and Results Data from 40 liver transplant recipients were collected. Mean albumin dose administered was 190.9 ± 162.3 g. No statistical differences were identified in patients receiving less than 140 g (n = 20) or more than 140 g (n = 20) with respect to demographic data other than gender and ethnicity. The mean APACHE III (Acute Physiology and Chronic Health) score was 69.7 ± 24.3. Approximately 70 episodes of morbidity and 23 readmissions were observed. Regardless of the APACHE III score, albumin was associated with increased overall morbidity and cardiovascular complications. Liver transplant recipients receiving more than 140 g had a longer hospital stay (14 vs 8 days, P = .025) and intensive care unit stay (6 vs 3 days, P = .051) than patients receiving 140 g or less. No correlation with risk of acute rejection was seen with albumin or tacrolimus. Conclusion Albumin supplementation among liver transplant recipients was associated with a significant risk for cardiovascular complications and overall number of complications regardless of APACHE III score. Future prospective studies are needed to further define the potential risk for complications in this patient population.
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Affiliation(s)
- Peter N Johnson
- University of Oklahoma, College of Pharmacy, Oklahoma City, USA
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30
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Al Tayeb H, El Dorry A, Amer N, Mowafy N, Zimaity M, Bayoumy E, Saleh SA. Autologous Stem Cells Transplantation in Egyptian Patients with Liver Cirrhosis on Top of Hepatitis C Virus. Int J Stem Cells 2015; 8:209-18. [PMID: 26634069 PMCID: PMC4651285 DOI: 10.15283/ijsc.2015.8.2.209] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background and Objectives Use of pluripotent stem cells is an ideal solution for liver insufficiencies. This work aims is to evaluate the safety and feasibility of autologous stem cells transplantation (SCT) in Egyptian patients of liver cirrhosis on top of hepatitis C virus (HCV). Subjects and Results 20 patients with HCV induced liver cirrhosis were divided into 2 groups. Group I: included 10 patients with liver cirrhosis Child score ≥9, for whom autologous stem cell transplantation was done using granulocyte colony stimulating factor (G-CSF) for stem cells mobilization. Separation and collection of the peripheral blood stem cells was done by leukapheresis. G-CSF mobilized peripheral blood mononuclear cells (G-CSF PB-MNCs) were counted by flow cytometry. Stem cell injection into the hepatic artery was done. Group II: included 10 patients with HCV induced liver cirrhosis as a control group. Follow up and comparison between both groups were done over a follow up period of 6 months. The procedure was well tolerated. Mobilization was successful and the total number of G-CSF PB-MNCs in the harvests ranged from 25×106 to 191×106. There was improvement in the quality of life, serum albumin, total bilirubin, liver enzymes and the Child-Pugh score of group I over the first two-three months after the procedure. Conclusion SCT in HCV induced liver cirrhosis is a safe procedure. It can improve the quality of life and hepatic functions transiently with no effect on the life expectancy or the fate of the liver cirrhosis.
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Affiliation(s)
- Hoda Al Tayeb
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Ahmed El Dorry
- Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nehad Amer
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Nadia Mowafy
- Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Maha Zimaity
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Essam Bayoumy
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Shereen A Saleh
- Department of Internal Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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31
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Xue HL, Zeng WZ, Wu XL, Jiang MD, Zheng SM, Zhang Y, Li HY. Clinical therapeutic effects of human umbilical cord-derived mesenchymal stem cells transplantation in the treatment of end-stage liver disease. Transplant Proc 2015; 47:412-8. [PMID: 25769583 DOI: 10.1016/j.transproceed.2014.10.048] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Revised: 10/08/2014] [Accepted: 10/28/2014] [Indexed: 02/07/2023]
Abstract
We aimed to evaluate clinical therapeutic effects of human umbilical cord-derived mesenchymal stem cell (UCMSC) transplantation in the treatment of end-stage liver diseases. The human UCMSCs were cultured and prepared, and then transplanted into the hepatic tissues of 50 patients with decompensated cirrhosis. The liver function, thrombin function, Model for End-Stage Liver Disease (MELD) score, and hemodynamic index value were detected during a 24-week follow-up period, with the addition of hepatoprotective, antiviral, and other conventional treatments. No complications or serious side effects were observed. In the first 2-3 weeks after surgery, symptoms including abdominal distension, oliguria, edema, and others decreased significantly, with increased appetite compared with before surgery. In the 24-week follow-up period, the levels of serum albumin and prealbumin increased significantly compared with the preoperative levels; the decrease of coagulation indicators was not significant. The MELD scores were also markedly increased. Alpha-fetoprotein levels increased without significance after treatment. There was no significant difference in the hemodynamic changes in the portal and splenic veins according to ultrasound. Moreover, no significant differences in the liver and thrombin functions between the hepatitis B virus group and the other-etiology group were observed.
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Affiliation(s)
- H-L Xue
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China
| | - W-Z Zeng
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China.
| | - X-L Wu
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China
| | - M-D Jiang
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China
| | - S-M Zheng
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China
| | - Y Zhang
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China
| | - H-Y Li
- Department of Gastroenterology, Chengdu Military General Hospital, Chengdu, Sichuan Province, People's Republic of China
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32
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Comorbidities have a limited impact on post-transplant survival in carefully selected cirrhotic patients: a population-based cohort study. Ann Hepatol 2015. [DOI: 10.1016/s1665-2681(19)31172-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2023]
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33
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Zeng W, Xiao J, Zheng G, Xing F, Tipoe GL, Wang X, He C, Chen ZY, Liu Y. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci Rep 2015; 5:11100. [PMID: 26057841 PMCID: PMC4460871 DOI: 10.1038/srep11100] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023] Open
Abstract
One of the major problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is partly attributed to insufficient resistance of transplanted stem cells to oxidative and inflammatory stresses at the injured sites. In the current study, we demonstrated the pivotal role of antioxidant levels in human umbilical cord mesenchymal stem cells (hUCMSCs) dynamic in vitro anti-stress abilities against lipopolysaccharide (LPS)/H2O2 intoxication and in vivo therapeutic efficacy in a murine acute liver failure model induced by D-galactosamine/LPS (Gal/LPS) by either reducing the antioxidant levels with diethyl maleate (DEM) or increasing antioxidant levels with edaravone. Both the anti- and pro-oxidant treatments dramatically influenced the survival, apoptosis, and reactive oxygen species (ROS) production of hUCMSCs through the MAPK-PKC-Nrf2 pathway in vitro. When compared with untreated and DEM-treated cells, edaravone-treated hUCMSCs rescued NOD/SCID mice from Gal/LPS-induced death, significantly improved hepatic functions and promoted host liver regeneration. These effects were probably from increased stem cell homing, promoted proliferation, decreased apoptosis and enhanced secretion of hepatocyte growth factor (HGF) under hepatic stress environment. In conclusion, elevating levels of antioxidants in hUCMSCs with edaravone can significantly influence their hepatic tissue repair capacity.
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Affiliation(s)
- Wen Zeng
- State key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.,Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jia Xiao
- State key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.,Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.,Department of Anatomy, The University of Hong Kong, Hong Kong, China
| | - Gang Zheng
- Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Feiyue Xing
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - George L Tipoe
- Department of Anatomy, The University of Hong Kong, Hong Kong, China
| | - Xiaogang Wang
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Chengyi He
- Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Zhi-Ying Chen
- Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yingxia Liu
- State key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
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34
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Ali JM, Davies SE, Brais RJ, Randle LV, Klinck JR, Allison MED, Chen Y, Pasea L, Harper SFJ, Pettigrew GJ. Analysis of ischemia/reperfusion injury in time-zero biopsies predicts liver allograft outcomes. Liver Transpl 2015; 21:487-99. [PMID: 25545865 DOI: 10.1002/lt.24072] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2014] [Revised: 12/04/2014] [Accepted: 12/14/2014] [Indexed: 12/12/2022]
Abstract
Ischemia/reperfusion injury (IRI) that develops after liver implantation may prejudice long-term graft survival, but it remains poorly understood. Here we correlate the severity of IRIs that were determined by histological grading of time-zero biopsies sampled after graft revascularization with patient and graft outcomes. Time-zero biopsies of 476 liver transplants performed at our center between 2000 and 2010 were graded as follows: nil (10.5%), mild (58.8%), moderate (26.1%), and severe (4.6%). Severe IRI was associated with donor age, donation after circulatory death, prolonged cold ischemia time, and liver steatosis, but it was also associated with increased rates of primary nonfunction (9.1%) and retransplantation within 90 days (22.7%). Longer term outcomes in the severe IRI group were also poor, with 1-year graft and patient survival rates of only 55% and 68%, respectively (cf. 90% and 93% for the remainder). Severe IRI on the time-zero biopsy was, in a multivariate analysis, an independent determinant of 1-year graft survival and was a better predictor of 1-year graft loss than liver steatosis, early graft dysfunction syndrome, and high first-week alanine aminotransferase with a positive predictive value of 45%. Time-zero biopsies predict adverse clinical outcomes after liver transplantation, and severe IRI upon biopsy signals the likely need for early retransplantation.
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Affiliation(s)
- Jason M Ali
- Departments of Surgery, Cambridge University Hospitals National Health Service Trust, Cambridge, United Kingdom
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35
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Zhang S, Zhang B, Chen X, Chen L, Wang Z, Wang Y. Three-dimensional culture in a microgravity bioreactor improves the engraftment efficiency of hepatic tissue constructs in mice. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2014; 25:2699-2709. [PMID: 25056199 DOI: 10.1007/s10856-014-5279-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2014] [Accepted: 07/13/2014] [Indexed: 06/03/2023]
Abstract
Tissue-engineered liver using primary hepatocytes has been considered a valuable new therapeutic modality as an alternative to whole organ liver transplantation for different liver diseases. The development of clinically feasible liver tissue engineering approaches, however, has been hampered by the poor engraftment efficiency of hepatocytes. We developed a three-dimensional (3D) culture system using a microgravity bioreactor (MB), biodegradable scaffolds and growth-factor-reduced Matrigel to construct a tissue-engineered liver for transplantation into the peritoneal cavity of non-obese diabetic severe combined immunodeficient mice. The number of viable cells in the hepatic tissue constructs was stably maintained in the 3D MB culture system. Hematoxylin-eosin staining and zonula occludens-1 expression revealed that neonatal mouse liver cells were reorganized to form tissue-like structures during MB culture. Significantly upregulated hepatic functions (albumin secretion, urea production and cytochrome P450 activity) were observed in the MB culture group. Post-transplantation analysis indicated that the engraftment efficiency of the hepatic tissue constructs prepared in MB cultures was higher than that of those prepared in the static cultures. Higher level of hepatic function in the implants was confirmed by the expression of albumin. These findings suggest that 3D MB culture systems may offer an improved method for creating tissue-engineered liver because of the higher engraftment efficiency and the reduction of the initial cell function loss.
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Affiliation(s)
- Shichang Zhang
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China,
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Kim SJ, Park MH, Moon HJ, Park JH, Ko DY, Jeong B. Polypeptide thermogels as a three dimensional culture scaffold for hepatogenic differentiation of human tonsil-derived mesenchymal stem cells. ACS APPLIED MATERIALS & INTERFACES 2014; 6:17034-17043. [PMID: 25192309 DOI: 10.1021/am504652y] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Tonsil-derived mesenchymal stem cells (TMSCs) were investigated for hepatogenic differentiation in the 3D matrixes of poly(ethylene glycol)-b-poly(l-alanine) (PEG-L-PA) thermogel. The diblock polymer formed β-sheet based fibrous nanoassemblies in water, and the aqueous polymer solution undergoes sol-to-gel transition as the temperature increases in a concentration range of 5.0-8.0 wt %. The cell-encapsulated 3D matrix was prepared by increasing the temperature of the cell-suspended PEG-L-PA aqueous solution (6.0 wt %) to 37 °C. The gel modulus at 37 °C was about 1000 Pa, which was similar to that of decellularized liver tissue. Cell proliferation, changes in cell morphology, hepatogenic biomarker expressions, and hepatocyte-specific biofunctions were compared for the following 3D culture systems: TMSC-encapsulated thermogels in the absence of hepatogenic growth factors (protocol M), TMSC-encapsulated thermogels where hepatogenic growth factors were supplied from the medium (protocol MGF), and TMSC-encapsulated thermogels where hepatogenic growth factors were coencapsulated with TMSCs during the sol-to-gel transition (protocol GGF). The spherical morphology and size of the encapsulated cells were maintained in the M system during the 3D culture period of 28 days, whereas the cells changed their morphology and significant aggregation of cells was observed in the MGF and GGF systems. The hepatocyte-specific biomarker expressions and metabolic functions were negligible for the M system. However, hepatogenic genes of albumin, cytokeratin 18 (CK-18), and hepatocyte nuclear factor 4α (HNF 4α) were significantly expressed in both MGF and GGF systems. In addition, production of albumin and α-fetoprotein was also significantly observed in both MGF and GGF systems. The uptake of cardiogreen and low-density lipoprotein, typical metabolic functions of hepatocytes, was apparent for MGF and GGF. The above data indicate that the 3D culture system of PEG-L-PA thermogels provides cytocompatible microenvironments for hepatogenic differentiation of TMSCs. In particular, the successful results of the GGF system suggest that the PEG-L-PA thermogel can be a promising injectable tissue engineering system for liver tissue regeneration after optimizing the aqueous formulation of TMSCs, hepatogenic growth factors, and other biochemicals.
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Affiliation(s)
- Seung-Jin Kim
- Department of Chemistry and Nano Science, Ewha Womans University , Global Top 5 Research Program, 52 Ewhayeodae-gil, Seodaemun-gu, Seoul, 120-750, Korea
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Bhushan B, Walesky C, Manley M, Gallagher T, Borude P, Edwards G, Monga SPS, Apte U. Pro-regenerative signaling after acetaminophen-induced acute liver injury in mice identified using a novel incremental dose model. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:3013-25. [PMID: 25193591 DOI: 10.1016/j.ajpath.2014.07.019] [Citation(s) in RCA: 140] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 06/23/2014] [Accepted: 07/15/2014] [Indexed: 12/12/2022]
Abstract
Acetaminophen (APAP) overdose results in acute liver failure and has limited treatment options. Previous studies show that stimulating liver regeneration is critical for survival after APAP overdose, but the mechanisms remain unclear. In this study, we identified major signaling pathways involved in liver regeneration after APAP-induced acute liver injury using a novel incremental dose model. Liver injury and regeneration were studied in C57BL/6 mice treated with either 300 mg/kg (APAP300) or 600 mg/kg (APAP600) APAP. Mice treated with APAP300 developed extensive liver injury and robust liver regeneration. In contrast, APAP600-treated mice exhibited significant liver injury but substantial inhibition of liver regeneration, resulting in sustained injury and decreased survival. The inhibition of liver regeneration in the APAP600 group was associated with cell cycle arrest and decreased cyclin D1 expression. Several known regenerative pathways, including the IL-6/STAT-3 and epidermal growth factor receptor/c-Met/mitogen-activated protein kinase pathways, were activated, even at APAP600, where regeneration was inhibited. However, canonical Wnt/β-catenin and NF-κB pathways were activated only in APAP300-treated mice, where liver regeneration was stimulated. Furthermore, overexpression of a stable form of β-catenin, where serine 45 is mutated to aspartic acid, in mice resulted in improved liver regeneration after APAP overdose. Taken together, our incremental dose model has identified a differential role of several signaling pathways in liver regeneration after APAP overdose and highlighted canonical Wnt signaling as a potential target for regenerative therapies for APAP-induced acute liver failure.
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Affiliation(s)
- Bharat Bhushan
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Chad Walesky
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Michael Manley
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Tara Gallagher
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Prachi Borude
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Genea Edwards
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Satdarshan P S Monga
- Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Udayan Apte
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas.
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Parés A, Mas A. Extracorporeal liver support in severe alcoholic hepatitis. World J Gastroenterol 2014; 20:8011-8017. [PMID: 25009371 PMCID: PMC4081670 DOI: 10.3748/wjg.v20.i25.8011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 02/27/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
The severity of alcoholic hepatitis (AH) which may coexist with cirrhosis varies greatly, from asymptomatic forms which are detected in alcoholic patients without any sign of liver disease, except laboratory abnormalities, to severe forms characterised by deep jaundice, ascites, hepatic encephalopathy and low prothrombin index. In hospitalized patients the mortality could be as high as 75%. The elevated number of therapeutic proposals reported for more than forty years reveals the lack of efficacy of a particular modality. Even in the most favorable trials, the survival is already very poor and in some cases related to the development of renal failure or hepatorenal syndrome. There are some motivating reports concerning albumin dialysis as a support treatment in patients with severe AH, either alone or in combination with other pharmacological therapies. The favorable effects of albumin dialysis in patients with severe AH suggest that the procedure used alone or in combination with other therapies may have a role in this clinical condition. This will be particularly relevant to offer an alternative therapy in these patients, thus being a potential bridge to recovery or to be listed for liver transplantation.
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Cardoso FS, Karvellas CJ, Kneteman NM, Meeberg G, Fidalgo P, Bagshaw SM. Respiratory rate at intensive care unit discharge after liver transplant is an independent risk factor for intensive care unit readmission within the same hospital stay: a nested case-control study. J Crit Care 2014; 29:791-6. [PMID: 24857401 DOI: 10.1016/j.jcrc.2014.03.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 03/08/2014] [Accepted: 03/16/2014] [Indexed: 12/29/2022]
Abstract
PURPOSE Intensive care unit (ICU) readmission negatively impacts patients' outcomes. We aimed to characterize and determine risk factors for ICU readmission within the initial hospital stay after liver transplant (LT). MATERIALS AND METHODS The reference cohort included 369 LT recipients from a Canadian center between 2005 and 2012. One control was randomly selected per each case of ICU readmission within the initial hospital stay after LT. Survival analysis used the Kaplan-Meier method. Associations were studied by conditional logistic regression. RESULTS Fifty-two (14%) LT recipients were readmitted to the ICU within the initial hospital stay after LT; they had longer first hospital stay (P < .001) and lower 1-month to 2-year cumulative survival (P < .001). Respiratory failure was the major cause of ICU readmission (61%). Respiratory rate at discharge from the first ICU stay after LT was an independent risk factor for ICU readmission (odds ratio = 1.24). The cutoff point more than 20 breaths per minute prognosticated ICU readmission with a specificity of 90% and a positive predictive value of 80%. CONCLUSIONS Intensive care unit readmission within the initial hospital stay after LT negatively impacts LT recipients' outcomes. Monitoring respiratory rate at discharge from the first ICU stay after LT is important to prevent readmission.
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Affiliation(s)
- Filipe S Cardoso
- Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, 3C1.12 Walter C Mackenzie Center, 8440-112 ST NW, Edmonton, Alberta, T6G-2B7, Canada.
| | - Constantine J Karvellas
- Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, 3C1.12 Walter C Mackenzie Center, 8440-112 ST NW, Edmonton, Alberta, T6G-2B7, Canada; Division of Gastroenterology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, 130 University Campus NW, Edmonton, Alberta, T6G-2X8, Canada.
| | - Norman M Kneteman
- Division of Transplantation, Department of Surgery, University of Alberta, Edmonton, Alberta, T6G-2B7, Canada.
| | - Glenda Meeberg
- Liver Transplant Program, Alberta Health Services, Edmonton, Alberta, T6G-2B7, Canada.
| | - Pedro Fidalgo
- Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, 3C1.12 Walter C Mackenzie Center, 8440-112 ST NW, Edmonton, Alberta, T6G-2B7, Canada.
| | - Sean M Bagshaw
- Division of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, 3C1.12 Walter C Mackenzie Center, 8440-112 ST NW, Edmonton, Alberta, T6G-2B7, Canada.
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Tucci FA, Broering R, Lutterbeck M, Schlaak JF, Küppers R. Intrahepatic B-cell follicles of chronically hepatitis C virus-infected individuals lack signs of an ectopic germinal center reaction. Eur J Immunol 2014; 44:1842-50. [PMID: 24609763 DOI: 10.1002/eji.201344378] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 02/05/2014] [Accepted: 03/04/2014] [Indexed: 12/27/2022]
Affiliation(s)
- Felicia A. Tucci
- Institute of Cell Biology (Cancer Research); University of Duisburg-Essen; Essen Germany
| | - Ruth Broering
- Department of Gastroenterology and Hepatology; University of Duisburg-Essen; University Hospital; Essen Germany
| | - Melanie Lutterbeck
- Department of Gastroenterology and Hepatology; University of Duisburg-Essen; University Hospital; Essen Germany
| | - Joerg F. Schlaak
- Department of Gastroenterology and Hepatology; University of Duisburg-Essen; University Hospital; Essen Germany
| | - Ralf Küppers
- Institute of Cell Biology (Cancer Research); University of Duisburg-Essen; Essen Germany
- Centre for Medical Biotechnology (ZMB); University of Duisburg-Essen; Essen Germany
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Sun S, Chen G, Xu M, Qiao Y, Zheng S. Differentiation and migration of bone marrow mesenchymal stem cells transplanted through the spleen in rats with portal hypertension. PLoS One 2013; 8:e83523. [PMID: 24340101 PMCID: PMC3858351 DOI: 10.1371/journal.pone.0083523] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 11/05/2013] [Indexed: 12/31/2022] Open
Abstract
Aims The goals of this paper were to evaluate the differentiation of bone marrow mesenchymal stem cells (BMSCs) into hepatocyte-like cells invitro, and to determine whether stem cells can migrate and plant into the liver with portal hypertension accompanied by the end-stage of liver disease. Methods BMSCs were isolated from rats and amplified with hepatocyte growth factor (HGF) and fibroblast growth factor-4 (FGF-4). The expression of alpha-fetoprotein (AFP), cytokeratin 18 (CK-18), and albumin (ALB) was detected by immunofluorescence in induced cells. Rats were randomly divided into experimental (with common bile duct ligation) and control groups. After injection of fluorescence labeled cells, cell distribution was observed under a fluorescence microscope. The integrated optical density (IOD) and cell distribution scores were evaluated using Image-Pro Plus 6.0 software. The portal pressure was measured before the rats were killed. Results After being induced with HGF and FGF-4, the Golgi apparatus, endoplasmic reticulum, ribosomes, and mitochondria all significantly increased in the fifth generation cells. Immunofluorescent analysis showed that the induced cells expressed AFP, CK-18, and ALB. BMSCs were stained by CM-Dil, and the labeling rate was as high as 95.5%. The portal pressure in experimental group was much higher than that of the control group (18.04±2.35 vs. 9.75±1.40cm H2O p<0.01). The IOD of transplanted cells in the experimental group was also significantly higher than that of the control group (11.30±2.09×105 vs. 2.93±0.88×105, p<0.01). In addition, the cell distribution score in the experimental group was lower than that of the control group (1.99±0.36 vs. 2.36±0.27, P<0.05). Conclusions The combination of HGF and FGF-4 induces the differentiation of BMSCs into hepatocyte-like cells, which express AFP, CK-18, and ALB. In addition, the recruitment of BMSCs (after transplantation in the spleen) was improved in rats with portal hypertension.
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Affiliation(s)
- Song Sun
- Surgical Department, Children’s Hospital of Fudan University, Shanghai, China
| | - Gong Chen
- Surgical Department, Children’s Hospital of Fudan University, Shanghai, China
| | - Menghua Xu
- Surgical Department, Children’s Hospital of Fudan University, Shanghai, China
| | - Yingli Qiao
- Surgical Department, Children’s Hospital of Fudan University, Shanghai, China
| | - Shan Zheng
- Surgical Department, Children’s Hospital of Fudan University, Shanghai, China
- * E-mail:
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Kuehl AR, Abshagen K, Eipel C, Laschke MW, Menger MD, Laue M, Vollmar B. External inosculation as a feature of revascularization occurs after free transplantation of murine liver grafts. Am J Transplant 2013; 13:286-98. [PMID: 23205733 DOI: 10.1111/j.1600-6143.2012.04336.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2012] [Revised: 10/02/2012] [Accepted: 10/09/2012] [Indexed: 01/25/2023]
Abstract
The induction of angiogenesis is essential for successful engraftment of freely transplanted cells or cellular composites. How to augment angiogenesis to ensure an appropriate viability of the grafts is still under investigation. This study evaluated the proangiogenic capability of different syngeneic free liver transplants and elucidated the origin of the newly formed vascular network via use of an eGFP(+) /eGFP(-) (enhanced green fluorescent protein) cross-over design. Using intravital fluorescence microscopy, we found that neonatal and resected murine liver transplants implanted into dorsal skinfold chambers display a significantly enhanced vascularization compared to regular adult transplants. Immunohistochemically, less tissue hypoxia, apoptosis and macrophage infiltration was observed in the neonatal and resected transplants, which is in line with improved vascularization of those grafts. Additionally, electron microscopy revealed morphological hallmarks of liver cells. eGFP(+) liver transplants implanted on eGFP(-) recipients displayed vascular sprouting from the grafts themselves and connection to the recipients` microvasculature, which also undergoes transient proangiogenic response. This process is described as external inosculation, with microvessels exhibiting a chimeric nature of the endothelial lining. These data collectively show that proliferative stimulation is taking effect on angiogenic properties of free transplants and might provide a novel tool for modulating the revascularization of free grafts.
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Affiliation(s)
- A-R Kuehl
- Institute for Experimental Surgery, University of Rostock, Rostock, Germany
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Burra P, Arcidiacono D, Bizzaro D, Chioato T, Di Liddo R, Banerjee A, Cappon A, Bo P, Conconi MT, Parnigotto PP, Mirandola S, Gringeri E, Carraro A, Cillo U, Russo FP. Systemic administration of a novel human umbilical cord mesenchymal stem cells population accelerates the resolution of acute liver injury. BMC Gastroenterol 2012; 12:88. [PMID: 22788801 PMCID: PMC3458924 DOI: 10.1186/1471-230x-12-88] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 07/12/2012] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Hepatocytes and stem cells transplantation may be an alternative to liver transplantation in acute or chronic liver disease. We aimed to evaluate the therapeutic potential of mesenchymal stem cells from human umbilical cord (UCMSCs), a readily available source of mesenchymal stem cells, in the CCl4-induced acute liver injury model. METHODS Mesenchymal stem cells profile was analyzed by flow cytometry. In order to evaluate the capability of our UCMSCs to differentiate in hepatocytes, cells were seeded on three different supports, untreated plastic support, MatrigelTM and human liver acellular matrix. Cells were analyzed by immunocitochemistry for alpha-fetoprotein and albumin expression, qPCR for hepatocyte markers gene expression, Periodic Acid-Schiff staining for glycogen storage, ELISA for albumin detection and colorimetric assay for urea secretion.To assess the effects of undifferentiated UCMSCs in hepatic regeneration after an acute liver injury, we transplanted them via tail vein in mice injected intraperitoneally with a single dose of CCl4. Livers were analyzed by histological evaluation for damage quantification, immunostaining for Kupffer and stellate cells/liver myofibroblasts activation and for UCMSCs homing. Pro- and anti-inflammatory cytokines gene expression was evaluated by qPCR analysis and antioxidant enzyme activity was measured by catalase quantification.Data were analyzed by Mann-Whitney U-test, Kruskal-Wallis test and Cuzick's test followed by Bonferroni correction for multiple comparisons. RESULTS We have standardized the isolation procedure to obtain a cell population with hepatogenic properties prior to in vivo transplantation. When subjected to hepatogenic differentiation on untreated plastic support, UCMSCs differentiated in hepatocyte-like cells as demonstrated by their morphology, progressive up-regulation of mature hepatocyte markers, glycogen storage, albumin and urea secretion. However, cells seeded on 3D-supports showed a minor or negligible differentiation capacity.UCMSCs-transplanted mice showed a more rapid damage resolution, as shown by histological analysis, with a lower inflammation level and an increased catalase activity compared to CCl4-treated mice. CONCLUSIONS Our findings show that UCMSCs can be reliably isolated, have hepatogenic properties and following systemic administration are able to accelerate the resolution of an acute liver injury without any differentiation and manipulation. These features make UCMSCs strong candidates for future application in regenerative medicine for human acute liver disease.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology, Department of Surgical, Oncological and Gastroenterological Sciences, Padova University Hospital, Via Giustiniani 2, Padova, 35128, Italy.
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Transplantation of Co-Microencapsulated Hepatocytes and HUVECs for Treatment of Fulminant Hepatic Failure. Int J Artif Organs 2012; 35:458-65. [DOI: 10.5301/ijao.5000092] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2012] [Indexed: 11/20/2022]
Abstract
Purpose: Microencapsulated hepatocytes might solve immunological rejection, broadening a new perspective for the treatment of fulminant hepatic failure (FHF). However, the transplantation of microcapsulated hepatocytes is limited by low cell viability Nevertheless, the co-microencapsulation of hepatocytes and human umbilical vein endothelial cells (HUVECs) may make the treatment of FHF more promising. Methods: We prepared the microcapsules using the high-voltage electrostatic droplet spray method, transplanted the empty microcapsules, isolated hepatocytes, microcapsulated hepatocytes, and co-microencapsulated hepatocytes and HUVEC intraperitoneally into rat models of FHF induced by D-aminogalactose (D-gal). After 1, 3, and 7 days, and 2, 3, and 4 weeks posttransplantation, we calculated the mortality and assessed alanine aminotransferase (ALT), aspartate aminotransferase (AST), and albumin (ALB) levels in the serum of the model; evaluated the integrality and recovery of microcapsules; and stained with hematoxylin and eosin (H&E) the recovered microcapsules as well as the liver of the FHF rats. Results: Hepatocyte-specific functions, including the levels of ALT, AST, and ALB in the serum of the co-microencapsulation group, were significantly better than those in the other groups (p<0.05) from 2 to 4 weeks after transplantation. Moreover, cotransplantation of the microencapsulated hepatocytes and HUVECs decreased the mortality rate of the FHF rats. The recovered microcapsules were intact, and recovery was up to 90%. H&E staining showed that the microencapsulated cells were still alive, and the liver tissues had started to recover after 4 weeks posttransplantation. Conclusion: The microcapsules have good biocompatibility and immunoprotection to protect the hepatocytes from immunological rejection. Cotransplantation of the microencapsulated hepatocytes and HUVECs could decrease mortality rates and improve liver function in FHF.
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de Oliveira SA, de Freitas Souza BS, Sá Barreto EP, Kaneto CM, Neto HA, Azevedo CM, Guimarães ET, de Freitas LAR, Ribeiro-Dos-Santos R, Soares MBP. Reduction of galectin-3 expression and liver fibrosis after cell therapy in a mouse model of cirrhosis. Cytotherapy 2011; 14:339-49. [PMID: 22149185 DOI: 10.3109/14653249.2011.637668] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AIMS Cirrhosis, end-stage liver disease, is caused by different mechanisms of injury, associated with persistent inflammation. Galectin-3 is an important regulator of fibrosis that links chronic inflammation to fibrogenesis. We investigated the role of bone marrow cell (BMC) transplantation in chronic inflammation and hepatic fibrosis. METHODS Liver cirrhosis was induced by administration of carbon tetrachloride and ethanol to wild-type C57BL/6 or bone marrow chimeric mice. Bone marrow chimeras were generated by lethal irradiation and transplantation with BMC obtained from green fluorescent protein (GFP(+) )donors. Wild-type cirrhotic mice were transplanted with BMC without irradiation. Livers from chimeras and cirrhotic transplanted mice were obtained for evaluation of inflammation, fibrosis and regulatory factors [galectin-3, matrix metallopeptidase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β]. RESULTS The development of cirrhosis was associated with increased expression of galectin-3 by F4/80(+) cells and intense migration of BMC to the liver. Furthermore, when transplanted after the establishment of cirrhosis, BMC also migrated to the liver and localized within the fibrous septa. Two months after BMC therapy, cirrhotic mice had a significant reduction in liver fibrosis and expression of type I collagen. We did not find any difference in levels of TGF-β, TIMP-1 and MMP-9 between saline and BMC groups. However, the numbers of inflammatory cells, phagocytes and galectin-3(+) cells were markedly lower in the livers of cirrhotic mice treated with BMC. CONCLUSIONS Our results demonstrate an important role for BMC in the regulation of liver fibrosis and that transplantation of BMC can accelerate fibrosis regression through modulatory mechanisms.
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Terrier B, Joly F, Vazquez T, Benech P, Rosenzwajg M, Carpentier W, Garrido M, Ghillani-Dalbin P, Klatzmann D, Cacoub P, Saadoun D. Expansion of Functionally Anergic CD21−/lowMarginal Zone-like B Cell Clones in Hepatitis C Virus Infection-Related Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2011; 187:6550-63. [DOI: 10.4049/jimmunol.1102022] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Guan R, Lui HF. Treatment of hepatitis B in decompensated liver cirrhosis. Int J Hepatol 2011; 2011:918017. [PMID: 21994876 PMCID: PMC3170850 DOI: 10.4061/2011/918017] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 04/19/2011] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B infection progresses from an asymptomatic persistently infected state to chronic hepatitis, cirrhosis, decompensated liver disease, and/or hepatocellular carcinoma. About 3% of patients with chronic hepatitis develop cirrhosis yearly, and about 5% of individuals with hepatitis B cirrhosis become decompensated annually. The outcome for patients with decompensated cirrhosis is bleak. Lamivudine, the first oral antiviral agent available for hepatitis B treatment is safe and effective and can improve or stabilize liver disease in patients with advanced cirrhosis and viraemia. Viral resistance restricts its prolonged use. Entecavir and tenofovir are newer agents with excellent resistance profile to date. These and some other antiviral agents are being investigated for optimal use in this rather challenging patient group.
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Affiliation(s)
- Richard Guan
- Mount Elizabeth Hospital and Medical Centre, Singapore 228510
| | - Hock Foong Lui
- Gleneagles Hospital and Medical Centre, Singapore 258500
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Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with synthetic cohort. AIDS 2011; 25:777-86. [PMID: 21412058 DOI: 10.1097/qad.0b013e328344febb] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVES The relative success of liver transplantation in those with HIV compared to HIV-uninfected individuals remains a point of intense debate. We aimed to evaluate the effectiveness of liver transplantation in HIV-hepatitis co-infected patients using a meta-analysis and individual patient data meta-analysis as a synthetic cohort. METHODS We searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL, AIDSLINE (inception to 2010), AMED, CINAHL, TOXNET, Development and Reproductive Toxicology, Hazardous Substances Databank, Psych-info and relevant conferences. We included cohort studies and individual case-reports evaluating survival of co-infected transplant patients. We abstracted data on cohort and case demographics and outcomes. We pooled cohorts using a random-effects analysis and created a synthetic cohort of cases using individual patient data. We confirmed this with the pooled cohort analysis. RESULTS We included 15 cohort studies and 49 case series with individual patient data. At 12 months, 84.4% [95% confidence interval (CI) 81.1-87.8%] of patients had survived. Within the HIV-infected population evaluated, HIV-hepatitis B virus (HBV) co-infection was associated with optimal survival. In an adjusted model, individuals positive for HBV were 8.28 (95% CI 2.26-30.33) times more likely to survive when compared to those without HBV. Further, individuals with an undetectable HIV viral load at the time of transplantation were 2.89 (95% CI 1.41-5.91) times more likely to survive when compared to those with detectable HIV viremia. Hepatitis C virus was not a predictor of patient survival when adjusted for by other key predictors [0.54 (95% CI 0.17-1.80)].
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Chen YC, Tsai KL, Hung CW, Ding DC, Chen LH, Chang YL, Chen LK, Chiou SH. Induced pluripotent stem cells and regenerative medicine. ACTA ACUST UNITED AC 2011. [DOI: 10.1016/j.jcgg.2010.12.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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