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Liu Z, Fu Y, Yan M, Zhang S, Cai J, Chen G, Dong Z. microRNAs in kidney diseases: Regulation, therapeutics, and biomarker potential. Pharmacol Ther 2024; 262:108709. [PMID: 39181246 DOI: 10.1016/j.pharmthera.2024.108709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/01/2024] [Accepted: 08/20/2024] [Indexed: 08/27/2024]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a crucial role in regulating gene expression by inhibiting the translation of their specific target messenger RNAs. To date, numerous studies have demonstrated changes in the expression of miRNAs in the kidneys throughout the progression of both acute kidney injury (AKI) and chronic kidney disease (CKD) in both human patients and experimental models. The role of specific microRNAs in the pathogenesis of kidney diseases has also been demonstrated. Further studies have elucidated the regulation of these microRNAs in diseased kidneys. Besides, certain miRNAs are detected in plasma and/or urine in kidney diseases and are potential diagnostic biomarkers. In this review, we provide an overview of recent developments in our understanding of how miRNAs contribute to kidney diseases. We also explore the potential of miRNAs as both biomarkers and therapeutic targets for these conditions, and highlight future research directions.
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Affiliation(s)
- Zhiwen Liu
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
| | - Ying Fu
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Mingjuan Yan
- Changde Hospital, Xiangya School of Medicine, Central South University, China
| | - Subing Zhang
- Youxian People's Hospital, Youxian, Hunan 412300, China
| | - Juan Cai
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Guochun Chen
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital at Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, GA, USA.
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2
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Vidal-Correoso D, Mateo SV, Muñoz-Morales AM, Lucas-Ruiz F, Jover-Aguilar M, Alconchel F, Martínez-Alarcón L, Sánchez-Redondo S, Santos V, López-López V, Ríos-Zambudio A, Cascales P, Pons JA, Ramírez P, Pelegrín P, Peinado H, Baroja-Mazo A. Cell-specific Extracellular Vesicles and Their miRNA Cargo Released Into the Organ Preservation Solution During Cold Ischemia Storage as Biomarkers for Liver Transplant Outcomes. Transplantation 2024; 108:e301-e312. [PMID: 38578699 DOI: 10.1097/tp.0000000000005008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Abstract
BACKGROUND Liver transplantation (LT) is crucial for end-stage liver disease patients, but organ shortages persist. Donation after circulatory death (DCD) aims to broaden the donor pool but presents challenges. Complications like acute rejection, hepatic artery thrombosis, and biliary issues still impact posttransplant prognosis. Biomarkers, including extracellular vesicles (EVs) and microRNAs (miRNAs), show promise in understanding and monitoring posttransplant events. This study explores the role of EVs and their miRNA cargo in LT, including their potential as diagnostic tools. METHODS EVs from intrahepatic end-ischemic organ preservation solution (eiOPS) in 79 donated livers were detected using different techniques (nanosight tracking analysis, transmission electron microscopy, and flow cytometry). EV-derived miRNAs were identified by quantitative real time-polymerase chain reaction. Bioinformatics analysis was performed using the R platform. RESULTS Different-sized and origin-specific EVs were found in eiOPS, with significantly higher concentrations in DCD compared with donation after brain death organs. Additionally, several EV-associated miRNAs, including let-7d-5p , miR-28-5p , miR-200a-3p , miR-200b-3p , miR-200c-3p , and miR-429 , were overexpressed in DCD-derived eiOPS. These miRNAs also exhibited differential expression patterns in liver tissue biopsies. Pathway analysis revealed enrichment in signaling pathways involved in extracellular matrix organization and various cellular processes. Moreover, specific EVs and miRNAs correlated with clinical outcomes, including survival and early allograft dysfunction. A predictive model combining biomarkers and clinical variables showed promise in acute rejection detection after LT. CONCLUSIONS These findings provide new insights into the use of EVs and miRNAs as biomarkers and their possible influence on posttransplantation outcomes, potentially contributing to improved diagnostic approaches and personalized treatment strategies in LT.
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Affiliation(s)
- Daniel Vidal-Correoso
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
| | - Sandra V Mateo
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
| | - Ana M Muñoz-Morales
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
| | - Fernando Lucas-Ruiz
- Experimental Ophthalmology Group, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla) & Ophthalmology Department, Universidad de Murcia, Murcia, Spain
- Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marta Jover-Aguilar
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
| | - Felipe Alconchel
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Laura Martínez-Alarcón
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
| | - Sara Sánchez-Redondo
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Vanesa Santos
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Víctor López-López
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Antonio Ríos-Zambudio
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Pedro Cascales
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - José Antonio Pons
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- Hepatology and Liver Transplant Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Pablo Ramírez
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- General Surgery and Abdominal Solid Organ Transplantation Unit, University Clinical Hospital Virgen de la Arrixaca, Murcia, Spain
| | - Pablo Pelegrín
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
- Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, Murcia, Spain
| | - Héctor Peinado
- Microenvironment & Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Alberto Baroja-Mazo
- Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia (IMIB-Pascual Parrilla), Murcia, Spain
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3
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Swanson KJ, Zhong W, Mandelbrot DA, Parajuli S. Histopathological Features and Role of Allograft Kidney Biopsy Among Recipients With Prolonged Delayed Graft Function: A Review. Transplantation 2024; 108:1911-1921. [PMID: 38383958 DOI: 10.1097/tp.0000000000004928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/23/2024]
Abstract
Delayed graft function (DGF) is an early posttransplant complication predictive of adverse outcomes. This "acute kidney injury of transplantation" is often defined as allograft dysfunction requiring renal replacement within 7 d posttransplantation. DGF is an important area of study because it is emerging with efforts to expand the donor pool and address the supply-demand gap in kidney transplantation. DGF is often caused by severe kidney injury mechanisms because of multiple donors, recipients, and immunologic factors. The role of kidney biopsy, particularly in prolonged DGF, is an ongoing area of research and inquiry for clinicians and researchers alike to better define, manage, and predict outcomes of this early posttransplant event. This review aims to provide an in-depth, comprehensive summary of the literature to date on the histopathology of DGF and the role of kidney transplant biopsies in prolonged DGF.
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Affiliation(s)
- Kurtis J Swanson
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Weixiong Zhong
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Didier A Mandelbrot
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Sandesh Parajuli
- Department of Medicine, Division of Nephrology, University of Wisconsin School of Medicine and Public Health, Madison, WI
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4
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Roos FJM, van Tienderen GS, Wu H, Bordeu I, Vinke D, Albarinos LM, Monfils K, Niesten S, Smits R, Willemse J, Rosmark O, Westergren-Thorsson G, Kunz DJ, de Wit M, French PJ, Vallier L, IJzermans JNM, Bartfai R, Marks H, Simons BD, van Royen ME, Verstegen MMA, van der Laan LJW. Human branching cholangiocyte organoids recapitulate functional bile duct formation. Cell Stem Cell 2022; 29:776-794.e13. [PMID: 35523140 DOI: 10.1016/j.stem.2022.04.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 02/25/2022] [Accepted: 04/14/2022] [Indexed: 12/13/2022]
Abstract
Human cholangiocyte organoids show great promise for regenerative therapies and in vitro modeling of bile duct development and diseases. However, the cystic organoids lack the branching morphology of intrahepatic bile ducts (IHBDs). Here, we report establishing human branching cholangiocyte organoid (BRCO) cultures. BRCOs self-organize into complex tubular structures resembling the IHBD architecture. Single-cell transcriptomics and functional analysis showed high similarity to primary cholangiocytes, and importantly, the branching growth mimics aspects of tubular development and is dependent on JAG1/NOTCH2 signaling. When applied to cholangiocarcinoma tumor organoids, the morphology changes to an in vitro morphology like primary tumors. Moreover, these branching cholangiocarcinoma organoids (BRCCAOs) better match the transcriptomic profile of primary tumors and showed increased chemoresistance to gemcitabine and cisplatin. In conclusion, BRCOs recapitulate a complex process of branching morphogenesis in vitro. This provides an improved model to study tubular formation, bile duct functionality, and associated biliary diseases.
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Affiliation(s)
- Floris J M Roos
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands; Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Gilles S van Tienderen
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Haoyu Wu
- Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands
| | - Ignacio Bordeu
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Dina Vinke
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Laura Muñoz Albarinos
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Kathryn Monfils
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Sabrah Niesten
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Ron Smits
- Erasmus MC, University Medical Center Rotterdam, Department of Gastroenterology and Hepatology, Rotterdam, the Netherlands
| | - Jorke Willemse
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Oskar Rosmark
- Lung Biology, Department Experimental Medical Science, Lund University, Lund, Sweden
| | | | - Daniel J Kunz
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, University of Cambridge, Cambridge, UK
| | - Maurice de Wit
- Erasmus MC, University Medical Center Rotterdam, Department of Pathology, Rotterdam, the Netherlands
| | - Pim J French
- Erasmus MC, University Medical Center Rotterdam, Cancer Treatment Screening Facility, Department of Neurology, Rotterdam, the Netherlands
| | - Ludovic Vallier
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Jan N M IJzermans
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Richard Bartfai
- Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands
| | - Hendrik Marks
- Radboud University, Department of Molecular Biology, Nijmegen, the Netherlands
| | - Ben D Simons
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK
| | - Martin E van Royen
- Erasmus MC, University Medical Center Rotterdam, Department of Pathology, Rotterdam, the Netherlands
| | - Monique M A Verstegen
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands
| | - Luc J W van der Laan
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Surgery, Rotterdam, the Netherlands.
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5
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Rutman AK, Negi S, Saberi N, Khan K, Tchervenkov J, Paraskevas S. Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios. Front Immunol 2022; 13:784374. [PMID: 35281056 PMCID: PMC8906931 DOI: 10.3389/fimmu.2022.784374] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 02/03/2022] [Indexed: 01/18/2023] Open
Abstract
Delayed graft function (DGF) in kidney transplantation is associated with ischemic injury and carries long term functional and immunological risks. Extracellular vesicles (EV) released from allografts may signal a degree of ischemic stress, and are thought to play an important role in the development of anti-donor immunity. Here, we show that kidney perfusate-derived extracellular vesicles (KP-EV) express donor-specific human leukocyte antigen. KP-EV from kidneys that experience DGF increase the T-helper 17 (Th17) to T-regulatory (Treg) ratio in third party peripheral blood mononuclear cells to a greater degree than those from kidneys with immediate function. We report miR-218-5p upregulation in KP-EV of kidney transplant recipients with DGF. Levels of miR-218-5p in KP-EV inversely correlated with recipient eGFR at multiple time points following transplantation. Additionally, the degree of increase in Th17/Treg ratio by KP-EV positively correlated with miR-218-5p expression in KP-EV samples. Taken together, these data provide evidence that KP-EV may contribute to modulating immune responses in transplant recipients. This could lead to novel intervention strategies to inhibit DGF in order to improve graft function and survival.
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Affiliation(s)
- Alissa K Rutman
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Sarita Negi
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Nasim Saberi
- Department of Surgery, McGill University, Montréal, QC, Canada
| | - Kashif Khan
- Division of Cardiology and Cardiac Surgery, McGill University Health Centre, Montréal, QC, Canada
| | - Jean Tchervenkov
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
| | - Steven Paraskevas
- Department of Surgery, McGill University, Montréal, QC, Canada.,Transplantation Immunology Laboratory, Research Institute of the McGill University Health Centre, Montréal, QC, Canada
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6
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Roos FJM, Wu H, Willemse J, Lieshout R, Albarinos LAM, Kan Y, Poley J, Bruno MJ, de Jonge J, Bártfai R, Marks H, IJzermans JNM, Verstegen MMA, van der Laan LJW. Cholangiocyte organoids from human bile retain a local phenotype and can repopulate bile ducts in vitro. Clin Transl Med 2021; 11:e566. [PMID: 34954911 PMCID: PMC8710298 DOI: 10.1002/ctm2.566] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/19/2021] [Accepted: 08/23/2021] [Indexed: 12/28/2022] Open
Abstract
The well-established 3D organoid culture method enabled efficient expansion of cholangiocyte-like cells from intrahepatic (IHBD) and extrahepatic bile duct (EHBD) tissue biopsies. The extensive expansion capacity of these organoids enables various applications, from cholangiocyte disease modelling to bile duct tissue engineering. Recent research demonstrated the feasibility of culturing cholangiocyte organoids from bile, which was minimal-invasive collected via endoscopic retrograde pancreaticography (ERCP). However, a detailed analysis of these bile cholangiocyte organoids (BCOs) and the cellular region of origin was not yet demonstrated. In this study, we characterize BCOs and mirror them to the already established organoids initiated from IHBD- and EHBD-tissue. We demonstrate successful organoid-initiation from extrahepatic bile collected from gallbladder after resection and by ERCP or percutaneous transhepatic cholangiopathy from a variety of patients. BCOs initiated from these three sources of bile all show features similar to in vivo cholangiocytes. The regional-specific characteristics of the BCOs are reflected by the exclusive expression of regional common bile duct genes (HOXB2 and HOXB3) by ERCP-derived BCOs and gallbladder-derived BCOs expressing gallbladder-specific genes. Moreover, BCOs have limited hepatocyte-fate differentiation potential compared to intrahepatic cholangiocyte organoids. These results indicate that organoid-initiating cells in bile are likely of local (extrahepatic) origin and are not of intrahepatic origin. Regarding the functionality of organoid initiating cells in bile, we demonstrate that BCOs efficiently repopulate decellularized EHBD scaffolds and restore the monolayer of cholangiocyte-like cells in vitro. Bile samples obtained through minimally invasive procedures provide a safe and effective alternative source of cholangiocyte organoids. The shedding of (organoid-initiating) cholangiocytes in bile provides a convenient source of organoids for regenerative medicine.
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Affiliation(s)
- Floris J. M. Roos
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | - Haoyu Wu
- Department of Molecular Biology, Radboud UniversityNijmegenThe Netherlands
| | - Jorke Willemse
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | - Ruby Lieshout
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | | | - Yik‐Yang Kan
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | - Jan‐Werner Poley
- Erasmus MCDepartment of Gastroenterology and Hepatology, University Medical Center RotterdamRotterdamThe Netherlands
| | - Marco J. Bruno
- Erasmus MCDepartment of Gastroenterology and Hepatology, University Medical Center RotterdamRotterdamThe Netherlands
| | - Jeroen de Jonge
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | - Richard Bártfai
- Department of Molecular Biology, Radboud UniversityNijmegenThe Netherlands
| | - Hendrik Marks
- Department of Molecular Biology, Radboud UniversityNijmegenThe Netherlands
| | - Jan N. M. IJzermans
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | - Monique M. A. Verstegen
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
| | - Luc J. W. van der Laan
- Erasmus MCDepartment of Surgery, University Medical Center RotterdamRotterdamThe Netherlands
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7
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Roest HP, IJzermans JNM, van der Laan LJW. Evaluation of RNA isolation methods for microRNA quantification in a range of clinical biofluids. BMC Biotechnol 2021; 21:48. [PMID: 34362351 PMCID: PMC8344161 DOI: 10.1186/s12896-021-00706-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 07/12/2021] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Extracellular microRNAs (miRNAs), released from cells into biofluids, have emerged as promising biomarkers for diagnostic and prognostic purposes. Several RNA isolation methods are available for the analysis of these cell-free miRNAs by RT-qPCR. Not all methods, however, are equally suitable for different biofluids. Here, we extracted total RNA from four very diverse biofluids: serum, urine, bile, and graft preservation fluid (perfusate). Four different protocols were used: a phenol-chloroform extraction and alcohol precipitation in combination with a precipitation carrier (QP) and three different column-based isolation methods, one with phenol-chloroform extraction (RN) and two without (NG and CU). For this range of clinical biofluid samples, we evaluated the potential of these different RNA isolation methods assessing recovery efficiency and the co-purification of RT-qPCR inhibiting compounds. RESULTS Differences were observed between each of the RNA isolation methods in the recovery of cel-miR-39, a synthetic miRNA spiked in during the workup procedure, and for endogenous miRNAs. Co-purification of heparin, a known RT-qPCR inhibitor, was assessed using heparinase I during cDNA synthesis. RT-qPCR detection of synthetic miRNAs cel-miR-39, spiked in during RNA workup, cel-miR-54, spiked in during cDNA synthesis, and endogenous miRNAs was strongly improved in the presence of heparinase I for some, but not all, isolation methods. Other, co-isolated RT-qPCR inhibitors were not identified, except for biliverdin, which co-isolated from some bile samples with one of the methods. In addition, we observed that serum and urine contain compounds that enhance the binding of heparin to certain solid-phase columns. CONCLUSIONS For reliable measurements of miRNA-based biomarkers in biofluids, optimization of RNA isolation procedures is recommended as methods can differ in miRNA detection and in co-purification of RT-qPCR inhibitory compounds. Heparinase I treatment confirmed that heparin appeared to be the major RT-qPCR inhibiting compound, but also biliverdin, co-isolated from bile, could interfere with detection.
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Affiliation(s)
- Henk P Roest
- Department of Surgery, Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS), Erasmus MC - University Medical Center, P.O. Box 2040, Room Na-1005, 3000, CA, Rotterdam, the Netherlands.
| | - Jan N M IJzermans
- Department of Surgery, Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS), Erasmus MC - University Medical Center, P.O. Box 2040, Room Na-1005, 3000, CA, Rotterdam, the Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Laboratory of Experimental Transplantation and Intestinal Surgery (LETIS), Erasmus MC - University Medical Center, P.O. Box 2040, Room Na-1005, 3000, CA, Rotterdam, the Netherlands
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8
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Mezzolla V, Pontrelli P, Fiorentino M, Stasi A, Pesce F, Franzin R, Rascio F, Grandaliano G, Stallone G, Infante B, Gesualdo L, Castellano G. Emerging biomarkers of delayed graft function in kidney transplantation. Transplant Rev (Orlando) 2021; 35:100629. [PMID: 34118742 DOI: 10.1016/j.trre.2021.100629] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 05/10/2021] [Accepted: 05/24/2021] [Indexed: 01/10/2023]
Abstract
Delayed Graft Function (DGF) is one of the most common early complications in kidney transplantation, associated with poor graft outcomes, prolonged post-operative hospitalization and higher rejection rates. Given the severe shortage of high-quality organs for transplantation, DGF incidence is expected to raise in the next years because of the use of nonstandard kidneys from Extended Criteria Donors (ECD) and from Donors after Circulatory Death (DCD). Alongside conventional methods for the evaluation of renal allograft [e.g. serum creatinine Glomerular Filtration Rate (GFR), needle biopsy], recent advancements in omics technologies, including proteomics, metabolomics and transcriptomics, may allow to discover novel biomarkers associated with DGF occurrence, in order to identify early preclinical signs of renal dysfunction and to improve the quality of graft management. Here, we gather contributions from basic scientists and clinical researchers to describe new omics studies in renal transplantation, reporting the emerging biomarkers of DGF that may implement and improve conventional approaches.
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Affiliation(s)
- Valeria Mezzolla
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Paola Pontrelli
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Francesco Pesce
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Rossana Franzin
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Federica Rascio
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Giuseppe Grandaliano
- Department of Translational Medicine and Surgery, Università Cattolica Sacro Cuore, Rome, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Barbara Infante
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Bari 70124, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Sciences, University of Foggia, Italy.
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9
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Roos FJM, Bijvelds MJC, Verstegen MMA, Roest HP, Metselaar HJ, Polak WG, Jonge HRD, IJzermans JNM, van der Laan LJW. Impact of hypoxia and AMPK on CFTR-mediated bicarbonate secretion in human cholangiocyte organoids. Am J Physiol Gastrointest Liver Physiol 2021; 320:G741-G752. [PMID: 33655768 DOI: 10.1152/ajpgi.00389.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cholangiocytes express cystic fibrosis transmembrane conductance regulator (CFTR), which is involved in bicarbonate secretion for the protection against bile toxicity. During liver transplantation, prolonged hypoxia of the graft is associated with cholangiocyte loss and biliary complications. Hypoxia is known to diminish CFTR activity in the intestine, but whether it affects CFTR activity in cholangiocytes remains unknown. Thus, the aim of this study is to investigate the effect of hypoxia on CFTR activity in intrahepatic cholangiocyte organoids (ICOs) and test drug interventions to restore bicarbonate secretion. Fifteen different human ICOs were cultured as monolayers and ion channel [CFTR and anoctamin-1 (ANO1)] activity was determined using an Ussing chamber assay with or without AMP kinase (AMPK) inhibitor under hypoxic and oxygenated conditions. Bile toxicity was tested by apical exposure of cells to fresh human bile. Overall gene expression analysis showed a high similarity between ICOs and primary cholangiocytes. Under oxygenated conditions, both CFTR and ANO1 channels were responsible for forskolin and uridine-5'-triphosphate (UTP) UTP-activated anion secretion. Forskolin stimulation in the absence of intracellular chloride showed ion transport, indicating that bicarbonate could be secreted by CFTR. During hypoxia, CFTR activity significantly decreased (P = 0.01). Switching from oxygen to hypoxia during CFTR measurements reduced CFTR activity (P = 0.03). Consequently, cell death increased when ICO monolayers were exposed to bile during hypoxia compared with oxygen (P = 0.04). Importantly, addition of AMPK inhibitor restored CFTR-mediated anion secretion during hypoxia. ICOs provide an excellent model to study cholangiocyte anion channels and drug-related interventions. Here, we demonstrate that hypoxia affects cholangiocyte ion secretion, leaving cholangiocytes vulnerable to bile toxicity. The mechanistic insights from this model maybe relevant for hypoxia-related biliary injury during liver transplantation.NEW & NOTEWORTHY The previously described liver-derived organoids resemble primary cholangiocytes and should be properly named intrahepatic cholangiocyte organoids (ICOs). ICOs have functional cholangiocyte ion channels (CFTR and ANO1). CFTR might be able to secrete bicarbonate directly into the bile duct lumen. Hypoxia inhibits CFTR and ANO1 functionality in ICOs, which can partially be restored by addition of an AMP kinase inhibitor. Hypoxia impairs cholangiocyte resistance against cytotoxic effects of bile, resulting in increased cell death.
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Affiliation(s)
- Floris J M Roos
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Marcel J C Bijvelds
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Henk P Roest
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Herold J Metselaar
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Wojciech G Polak
- Division of Hepato-Pancreato-Biliary and Transplant Surgery, Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Transplant Institute, Rotterdam, The Netherlands
| | - Hugo R de Jonge
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
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10
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Cardiac MicroRNA Expression Profile After Experimental Brain Death Is Associated With Myocardial Dysfunction and Can Be Modulated by Hypertonic Saline. Transplantation 2021; 106:289-298. [PMID: 33859149 DOI: 10.1097/tp.0000000000003779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Brain death (BD) is associated with systemic inflammatory compromise, which might affect the quality of the transplanted organs. This study investigated the expression profile of cardiac microRNAs (miRNAs) after BD, and their relationship with the observed decline in myocardial function and with the changes induced by hypertonic saline solution (HSS) treatment. METHODS Wistar rats were assigned to sham-operation (SHAM) or submitted to BD with and without the administration of HSS. Cardiac function was assessed for 6h with left ventricular (LV) pressure-volume analysis. We screened 641 rodent miRNAs to identify differentially expressed miRNAs (DEMs) in the heart and computational and functional analysis were performed to compare the DEMs and find their putative targets and their related enriched canonical pathways. RESULTS An enhanced expression in canonical pathways related to inflammation and myocardial apoptosis was observed in BD induced group, with two miRNAs, miR-30a-3p and miR-467f, correlating with the level of LV dysfunction observed after BD. Conversely, HSS treated after BD and SHAM groups showed similar enriched pathways related to the maintenance of heart homeostasis regulation, in agreement with the observation that both groups did not have significant changes in LV function. CONCLUSIONS These findings highlight the potential of miRNAs as biomarkers for assessing damage in BD donor hearts and to monitor the changes induced by therapeutic measures like HSS, opening a perspective to improve graft quality and to better understand the pathophysiology of BD. The possible relation of BD induced miRNA's on early and late cardiac allograft function must be investigated.Supplemental Visual Abstract; http://links.lww.com/TP/C210.
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11
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Palmisano A, Gandolfini I, Delsante M, Cantarelli C, Fiaccadori E, Cravedi P, Maggiore U. Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes. J Clin Med 2021; 10:1484. [PMID: 33918444 PMCID: PMC8038198 DOI: 10.3390/jcm10071484] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.
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Affiliation(s)
- Alessandra Palmisano
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
| | - Ilaria Gandolfini
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
| | - Marco Delsante
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
| | - Chiara Cantarelli
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
| | - Enrico Fiaccadori
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
| | - Paolo Cravedi
- Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
| | - Umberto Maggiore
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (I.G.); (M.D.); (C.C.); (E.F.); (U.M.)
- Nephrology Unit, Parma University Hospital, 43126 Parma, Italy
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12
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Roos FJM, Verstegen MMA, Muñoz Albarinos L, Roest HP, Poley JW, Tetteroo GWM, IJzermans JNM, van der Laan LJW. Human Bile Contains Cholangiocyte Organoid-Initiating Cells Which Expand as Functional Cholangiocytes in Non-canonical Wnt Stimulating Conditions. Front Cell Dev Biol 2021; 8:630492. [PMID: 33634107 PMCID: PMC7900156 DOI: 10.3389/fcell.2020.630492] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 12/31/2020] [Indexed: 12/12/2022] Open
Abstract
Diseases of the bile duct (cholangiopathies) remain a common indication for liver transplantation, while little progress has been made over the last decade in understanding the underlying pathophysiology. This is largely due to lack of proper in vitro model systems to study cholangiopathies. Recently, a culture method has been developed that allows for expansion of human bile duct epithelial cells grown as extrahepatic cholangiocyte organoids (ncECOs) in non-canonical Wnt-stimulating conditions. These ncECOs closely resemble cholangiocytes in culture and have shown to efficiently repopulate collagen scaffolds that could act as functional biliary tissue in mice. Thus far, initiation of ncECOs required tissue samples, thereby limiting broad patient-specific applications. Here, we report that bile fluid, which can be less invasively obtained and with low risk for the patients, is an alternative source for culturing ncECOs. Further characterization showed that bile-derived cholangiocyte organoids (ncBCOs) are highly similar to ncECOs obtained from bile duct tissue biopsies. Compared to the previously reported bile-cholangiocyte organoids cultured in canonical Wnt-stimulation conditions, ncBCOs have superior function of cholangiocyte ion channels and are able to respond to secretin and somatostatin. In conclusion, bile is a new, less invasive, source for patient-derived cholangiocyte organoids and makes their regenerative medicine applications more safe and feasible.
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Affiliation(s)
- Floris J M Roos
- Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Monique M A Verstegen
- Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Laura Muñoz Albarinos
- Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Henk P Roest
- Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Jan-Werner Poley
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Geert W M Tetteroo
- Department of Surgery, IJsselland Hospital, Capelle aan den IJssel, Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, Netherlands
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13
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Swanson KJ, Aziz F, Garg N, Mohamed M, Mandelbrot D, Djamali A, Parajuli S. Role of novel biomarkers in kidney transplantation. World J Transplant 2020; 10:230-255. [PMID: 32995319 PMCID: PMC7504189 DOI: 10.5500/wjt.v10.i9.230] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 07/21/2020] [Accepted: 08/25/2020] [Indexed: 02/05/2023] Open
Abstract
Clinical application of biomarkers is an integral component of transplant care. Clinicians and scientists alike are in search of better biomarkers than the current serologic (serum creatinine, donor-specific antibodies), urine-derived (urinalysis, urine protein), and histologic ones we now use. The science behind recent biomarker discovery spans across multiple molecular biologic disciplines, including transcriptomics, proteomics, and metabolomics. Innovative methodology and integration of basic and clinical approaches have allowed researchers to unearth molecular phenomena preceding clinical disease. Biomarkers can be classified in several ways. In this review, we have classified them via their origin and outcome: Primarily immunologic, i.e., representative of immune regulation and dysfunction and non-immunologic, pertaining to delayed graft function, cardiovascular events/mortality, infection, malignancy, post-transplant diabetes, graft, and patient survival. Novel biomarker uses to guide the diagnosis and management of transplant-related outcomes is a promising area of research. However, the use of biomarkers to predict outcomes after kidney transplantation is not well studied. In this review, we summarize the recent studies illustrating biomarker use and transplant outcomes.
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Affiliation(s)
- Kurtis J Swanson
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Fahad Aziz
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Neetika Garg
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Maha Mohamed
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Didier Mandelbrot
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Arjang Djamali
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Sandesh Parajuli
- Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
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Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction. Int J Mol Sci 2020; 21:ijms21155404. [PMID: 32751357 PMCID: PMC7432796 DOI: 10.3390/ijms21155404] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/22/2020] [Accepted: 07/27/2020] [Indexed: 02/06/2023] Open
Abstract
New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.
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15
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Diagnostic, Prognostic, and Therapeutic Value of Non-Coding RNA Expression Profiles in Renal Transplantation. Diagnostics (Basel) 2020; 10:diagnostics10020060. [PMID: 31978997 PMCID: PMC7168890 DOI: 10.3390/diagnostics10020060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 01/17/2020] [Accepted: 01/19/2020] [Indexed: 02/06/2023] Open
Abstract
End-stage renal disease is a public health problem responsible for millions of deaths worldwide each year. Although transplantation is the preferred treatment for patients in need of renal replacement therapy, long-term allograft survival remains challenging. Advances in high-throughput methods for large-scale molecular data generation and computational analysis are promising to overcome the current limitations posed by conventional diagnostic and disease classifications post-transplantation. Non-coding RNAs (ncRNAs) are RNA molecules that, despite lacking protein-coding potential, are essential in the regulation of epigenetic, transcriptional, and post-translational mechanisms involved in both health and disease. A large body of evidence suggests that ncRNAs can act as biomarkers of renal injury and graft loss after transplantation. Hence, the focus of this review is to discuss the existing molecular signatures of non-coding transcripts and their value to improve diagnosis, predict the risk of rejection, and guide therapeutic choices post-transplantation.
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16
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Identification and Validation Model for Informative Liquid Biopsy-Based microRNA Biomarkers: Insights from Germ Cell Tumor In Vitro, In Vivo and Patient-Derived Data. Cells 2019; 8:cells8121637. [PMID: 31847394 PMCID: PMC6952794 DOI: 10.3390/cells8121637] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 12/11/2019] [Accepted: 12/13/2019] [Indexed: 12/26/2022] Open
Abstract
Liquid biopsy-based biomarkers, such as microRNAs, represent valuable tools for patient management, but often do not make it to integration in the clinic. We aim to explore issues impeding this transition, in the setting of germ cell tumors, for which novel biomarkers are needed. We describe a model for identifying and validating clinically relevant microRNAs for germ cell tumor patients, using both in vitro, in vivo (mouse model) and patient-derived data. Initial wide screening of candidate microRNAs is performed, followed by targeted profiling of potentially relevant biomarkers. We demonstrate the relevance of appropriate (negative) controls, experimental conditions (proliferation), and issues related to sample origin (serum, plasma, cerebral spinal fluid) and pre-analytical variables (hemolysis, contaminants, temperature), all of which could interfere with liquid biopsy-based studies and their conclusions. Finally, we show the value of our identification model in a specific scenario, contradicting the presumed role of miR-375 as marker of teratoma histology in liquid biopsy setting. Our findings indicate other putative microRNAs (miR-885-5p, miR-448 and miR-197-3p) fulfilling this clinical need. The identification model is informative to identify the best candidate microRNAs to pursue in a clinical setting.
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The Small RNA Repertoire of Small Extracellular Vesicles Isolated From Donor Kidney Preservation Fluid Provides a Source for Biomarker Discovery for Organ Quality and Posttransplantation Graft Function. Transplant Direct 2019; 5:e484. [PMID: 31579812 PMCID: PMC6739040 DOI: 10.1097/txd.0000000000000929] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 07/11/2019] [Indexed: 02/07/2023] Open
Abstract
Supplemental Digital Content is available in the text. Delayed graft function (DGF) after kidney transplantation is negatively associated with long-term graft function and survival. Kidney function after transplantation depends on multiple factors, both donor- and recipient-associated. Prediction of posttransplantation graft function would allow timely intervention to optimize patient care and survival. Currently, graft-based predictions can be made based on histological and molecular analyses of 0-hour biopsy samples. However, such analyses are currently not implemented, as biopsy samples represent only a very small portion of the entire graft and are not routinely analyzed in all transplantation centers. Alternatives are thus required.
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18
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Liu Z, Wang Y, Shu S, Cai J, Tang C, Dong Z. Non-coding RNAs in kidney injury and repair. Am J Physiol Cell Physiol 2019; 317:C177-C188. [PMID: 30969781 DOI: 10.1152/ajpcell.00048.2019] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Acute kidney injury (AKI) is a major kidney disease featured by a rapid decline of renal function. Pathologically, AKI is characterized by tubular epithelial cell injury and death. Besides its acute consequence, AKI contributes critically to the development and progression of chronic kidney disease (CKD). After AKI, surviving tubular cells regenerate to repair. Normal repair restores tubular integrity, while maladaptive or incomplete repair results in renal fibrosis and eventually CKD. Non-coding RNAs (ncRNAs) are functional RNA molecules that are transcribed from DNA but not translated into proteins, which mainly include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs), and tRNAs. Accumulating evidence suggests that ncRNAs play important roles in kidney injury and repair. In this review, we summarize the recent advances in the understanding of the roles of ncRNAs, especially miRNAs and lncRNAs in kidney injury and repair, discuss the potential application of ncRNAs as biomarkers of AKI as well as therapeutic targets for treating AKI and impeding AKI-CKD transition, and highlight the future research directions of ncRNAs in kidney injury and repair.
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Affiliation(s)
- Zhiwen Liu
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Ying Wang
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Shaoqun Shu
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Juan Cai
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Chengyuan Tang
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China
| | - Zheng Dong
- Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University , Changsha , China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center , Augusta, Georgia
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