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Merhej T, El Fekih R, Azzi JR. Urinary biomarkers of kidney transplant rejection. Curr Opin Organ Transplant 2025; 30:195-200. [PMID: 40173008 DOI: 10.1097/mot.0000000000001217] [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] [Indexed: 04/04/2025]
Abstract
PURPOSE OF REVIEW Despite the introduction of many new immunosuppressive medications, allograft rejection remains a significant complication in transplantation. The use of "liquid biopsy" to evaluate allograft function and detect early rejection has recently become a prominent focus of investigation as it holds promise in providing noninvasive and immediate insights into the cellular and molecular makeup of the graft. RECENT FINDINGS In recent years, the introduction of molecular medicine along with the use of new technologies, including high-throughput techniques, has not only accelerated biomarker discovery but has also contributed to improving our understanding of the mechanisms underlying immune rejection. Genomics, transcriptomics, and metabolomics approaches, along with the increasing use of machine learning techniques, have paved the way for the discovery and development of novel biomarkers. SUMMARY Each year, there are hundreds of new biomarker discoveries in the publications. However, only a small fraction can be practically used as clinical tests or surrogate endpoints, receive FDA approval, and reach clinical application. Well designed and reproducible discovery and validation studies are rare and crucial. A contributing factor could be poor study design or quality of biospecimen repositories. In this review, we discuss urinary biomarkers of kidney allograft rejection that have shown promising findings but have yet to be successfully transitioned from bench to bedside.
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Affiliation(s)
- Tamara Merhej
- Renal Division, Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Seifert ME, Kho AT, Sheward L, Rodig N, Goldberg S, Diehl M, Zurakowski D, Mannon RB, Dharnidharka VR, Bestard O, Blydt-Hansen TD, Briscoe DM. Combination Automated Microfluidics Measurement of Urine C-C Motif Ligand 2, CXC-Motif Chemokine 9, CXC-Motif Chemokine 10, and Vascular Endothelial Growth Factor A for Monitoring Patients with a Kidney Transplant. Clin J Am Soc Nephrol 2025; 20:719-732. [PMID: 40067364 PMCID: PMC12097184 DOI: 10.2215/cjn.0000000666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 03/06/2025] [Indexed: 05/09/2025]
Abstract
Key Points Combining urine C-C motif ligand 2, CXC-motif chemokine 9, CXC-motif chemokine 10, and vascular endothelial growth factor A identifies stable transplant recipients without biopsy-proven acute rejection with >75% specificity and 94% negative predictive value. Measuring four urine analytes in combination using an automated platform is highly efficient (<70 minutes) and reproducible across three independent sites. Automated urine analyte measurement provides critical decision support and outperforms eGFR measurements alone for post-transplantation monitoring. Background Recent studies indicate that up to 36% of pediatric and adult kidney transplant recipients with stable serum creatinine levels will have acute rejection detected on surveillance biopsy. The purpose of this study was to develop and validate a risk algorithm for identifying low- and high-risk patients using a novel automated platform that simultaneously measures urinary C-C motif ligand 2 (CCL2), CXC-motif chemokine 9 (CXCL9), CXC-motif chemokine 10 (CXCL10), and vascular endothelial growth factor A (VEGF-A) with high precision. Methods We designed a multicenter observational study to evaluate the performance of urinary CCL2, CXCL9, CXCL10, and VEGF-A in a training set of 517 banked samples collected at the time of surveillance or indication kidney biopsies from both adult and pediatric recipients. Risk algorithms combining all four analytes were developed in the training set and subsequently validated in three laboratory sites in two additional pediatric cohorts (N =174). Results The automated platform had remarkably high throughput, generating reproducible results in 60–70 minutes. Analysis was initially performed in the training set (N =517), which included biopsies read as normal (N =330), acute rejection (N =92), or borderline rejection (N =95). We found that each biomarker independently discriminated normal biopsies versus those with acute rejection (P < 10−5). A risk algorithm using all four biomarkers (score4) had excellent diagnostic performance for acute rejection in both for-cause and surveillance biopsies performed on patients with stable GFRs, outperforming any individual biomarker as well as estimated GFR assessments. Validation assays performed in the two additional pediatric cohorts in three laboratory sites demonstrated a robust correlation of results; score4 retained excellent diagnostic performance (75% specificity and 92% negative predictive value). Conclusions Automated measurements of urine CCL2, CXCL9, CXCL10, and VEGF-A can distinguish kidney transplant recipients at low versus high risk of rejection. We suggest that this assay can advantage clinical decision making in routine post-transplant monitoring because of its low cost, rapid throughput, and operator independence.
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Affiliation(s)
| | - Alvin T. Kho
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Lea Sheward
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nancy Rodig
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Sarah Goldberg
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Margaret Diehl
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - David Zurakowski
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Vikas R. Dharnidharka
- Washington University School of Medicine, St. Louis, Missouri; Current Address: Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | | | | | - David M. Briscoe
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
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Xu W, Boer K, Hesselink DA, Baan CC. Extracellular Vesicles and Immune Activation in Solid Organ Transplantation: The Impact of Immunosuppression. BioDrugs 2025; 39:445-459. [PMID: 40140222 PMCID: PMC12031870 DOI: 10.1007/s40259-025-00713-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2025] [Indexed: 03/28/2025]
Abstract
Recent advances in extracellular vesicle (EV) research in organ transplantation have highlighted the crucial role of donor-derived EVs in triggering alloimmune responses, ultimately contributing to transplant rejection. Following transplantation, EVs carrying donor major histocompatibility complex (MHC) molecules activate recipient antigen-presenting cells (APCs), initiating both alloreactive and regulatory T-cell responses. While immunosuppressive drugs are essential for preventing rejection, they may also influence the biogenesis and release of EVs from donor cells. This review examines the impact of maintenance immunosuppressive therapy on EV biogenesis and release post-transplantation. In addition, EV release and uptake may be influenced by specific factors such as the patient's end-stage organ disease and the transplant procedure itself. In-vitro studies using primary human parenchymal and immune cells-integrated with cutting-edge multi-omics techniques, including genomics, proteomics, lipidomics, and single-EV analysis-will offer deeper insights into EV biology and the mechanisms by which immunosuppressive agents regulate EV-initiated immune processes. A detailed understanding of how organ failure, the transplantation procedure and immunosuppressive drugs affect the biology of EVs may uncover new roles for EVs in immune activation and regulation in patients, ultimately leading to improved immunosuppressive strategies and better transplant outcomes.
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Affiliation(s)
- Weicheng Xu
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands.
| | - Karin Boer
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Sector Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam Erasmus MC, Doctor Molewaterplein 40, Room Nc 508, 3015 GD, Rotterdam, The Netherlands
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Cao H, Li Z, Ye J, Lv Y, Zhang C, Liang T, Wang Y. Emerging roles of exosomes in the diagnosis and treatment of kidney diseases. Front Pharmacol 2025; 16:1525314. [PMID: 40308771 PMCID: PMC12041035 DOI: 10.3389/fphar.2025.1525314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 03/20/2025] [Indexed: 05/02/2025] Open
Abstract
The complex etiology and spectrum of kidney diseases necessitate vigilant attention; the focus on early diagnosis and intervention in kidney diseases remains a critical issue in medical research. Recently, with the expanding studies on extracellular vesicles, exosomes have garnered increasing interest as a promising tool for the diagnosis and treatment of kidney diseases. Exosomes are nano-sized extracellular vesicles that transport a diverse array of bioactive substances, which can influence various pathological processes associated with kidney diseases and exhibit detrimental or beneficial effects. Within the kidney, exosomes derived from the glomeruli and renal tubules possess the ability to enter systemic circulation or urine. The biomarkers they carry can reflect alterations in the pathological state of the kidneys, thereby offering novel avenues for early diagnosis. Furthermore, research studies have confirmed that exosomes originating from multiple cell types exhibit therapeutic potential in treating kidney disease; notably, those derived from mesenchymal stem cells (MSCs) have shown significant treatment efficacy. This comprehensive review summarizes the contributions of exosomes from different cell types within the kidneys while exploring their physiological and pathological roles therein. Additionally, we emphasize recent advancements in exosome applications for the diagnosis and treatment of various forms of kidney diseases over the past decades. We not only introduce the urinary and blood biomarkers linked to kidney diseases found within exosomes but also explore their therapeutic effects. Finally, we discuss existing challenges and future directions concerning the clinical applications of exosomes for diagnostic and therapeutic purposes.
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Affiliation(s)
- Huanhuan Cao
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zixi Li
- Department of Clinical Laboratory, Traditional Chinese and Western Medicine Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiajia Ye
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yi Lv
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Liang
- Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yumei Wang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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El Fekih R, Franzen K, Hurley J, Haynes BC, Merhej T, Alghamdi A, Hallmark E, Xing S, Kumar S, Choi J, Solhjou Z, Deban C, Saad A, Halawi A, Younis N, Cashman K, Dagher M, Eskandari SK, Al Chaar S, Rennke H, Weins A, Abdi R, Chandraker A, Markmann JF, Safa K, Riella LV, McFaul M, Ventura C, Vlassov AV, Formica R, Macedo C, Skog J, Azzi JR. An Exosomal mRNA Urine Test for Detection and Risk Stratification of Human Kidney Transplant Rejection. Kidney Int Rep 2025; 10:1131-1142. [PMID: 40303229 PMCID: PMC12034883 DOI: 10.1016/j.ekir.2025.01.036] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 01/27/2025] [Indexed: 05/02/2025] Open
Abstract
Introduction We recently discovered 2 urinary exosomal mRNA signatures to identify and differentiate T-cell-mediated rejection (TCMR) from antibody-mediated rejection (ABMR) in kidney transplant recipients. Here, we developed Exosome Transplant Rejection Urine (ExoTRU), a urinetest based on a 4-gene signature from the previous discovery cohort, showed its clinical utility in a new cohort of kidney transplant recipients undergoing clinically indicated biopsies, and validated it through a separate laboratory in an independent-cohort of patients. Methods A workflow suited for clinical laboratories was developed, allowing for smaller urine volumes and widely standardized qPCR instrumentation. A total of 226 urine samples from 214 patients were paired with clinically indicated biopsies. Urinary exosomal mRNAs levels were evaluated for previously defined targets. Results Four mRNAs (IL32, B2M, CXCL11, and PGK1) performed well in distinguishing biopsies with rejection or significant inflammation from those without inflammation, achieving 94% sensitivity, 62% positive predictive value, and 52% specificity. Patients who tested positive by the signature but negative by biopsy were nearly twice as likely to experience adverse outcomes in the 5-year follow-up period, including subsequent rejection, thereby showing the limitations of kidney biopsies and the prognostic potential of molecular signatures. The evaluation of an independent validation cohort showed similar performance, achieving an area under the curve (AUC) of 0.838. Another 6-gene signature distinguished TCMR from ABMR, with an AUC of 0.756. Conclusion Exosomal mRNA gene signatures identified patients with different stages and classes of rejection, including early stage and significant inflammation, enabling improved decision-making and patient management and reducing unnecessary biopsies by 45%. This represents a potential tool for risk stratification based on poor outcomes in patients with positive signatures.
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Affiliation(s)
- Rania El Fekih
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kurt Franzen
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - James Hurley
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - Brian C. Haynes
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
- Asuragen, a Bio-Techne brand, Austin, Texas, USA
| | - Tamara Merhej
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Areej Alghamdi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Shuran Xing
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - Sonia Kumar
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - John Choi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Zhabiz Solhjou
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Christa Deban
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anis Saad
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ahmad Halawi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nour Younis
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Katherine Cashman
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Maribel Dagher
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Siawosh K. Eskandari
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Soltan Al Chaar
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Helmut Rennke
- Pathology Department, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Astrid Weins
- Pathology Department, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Reza Abdi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anil Chandraker
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - James F. Markmann
- Division of Transplant Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Kassem Safa
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Leonardo V. Riella
- Transplant Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Matt McFaul
- Thermo Fisher Scientific, West Hills, California, USA
| | - Chris Ventura
- Thermo Fisher Scientific, West Hills, California, USA
| | | | - Richard Formica
- Section of Nephrology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Camila Macedo
- Thomas Starzl E. Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Johan Skog
- Exosome Diagnostics, a Bio-Techne brand, Waltham, Massachusetts, USA
| | - Jamil R. Azzi
- Renal Division, Transplantation Research Center, Brigham and Women’s Hospital and Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Westphal SG, Mannon RB. Biomarkers of Rejection in Kidney Transplantation. Am J Kidney Dis 2025; 85:364-374. [PMID: 39419272 PMCID: PMC11846701 DOI: 10.1053/j.ajkd.2024.07.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/02/2024] [Accepted: 07/26/2024] [Indexed: 10/19/2024]
Abstract
Alloimmune injury is a major cause of long-term kidney allograft failure whether due to functionally stable (subclinical) or overt clinical rejection. These episodes may be mediated by immune cells (cellular rejection) or alloantibody (antibody-mediated rejection). Early recognition of immune injury is needed for timely appropriate intervention to maintain graft functional viability. However, the conventional measure of kidney function (ie, serum creatinine) is insufficient for immune monitoring due to limited sensitivity and specificity for rejection. As a result, there is need for biomarkers that more sensitively detect the immune response to the kidney allograft. Recently, several biomarkers have been clinically implemented into the care of kidney transplant recipients. These biomarkers attempt to achieve multiple goals including (1) more sensitive detection of clinical and subclinical rejection, (2) predicting impending rejection, (3) monitoring for the adequacy of treatment response, and (4) facilitating personalized immunosuppression. In this review, we summarize the findings to date in commercially available biomarkers, along with biomarkers approaching clinical implementation. While we discuss the analytical and clinical validity of these biomarkers, we identify the challenges and limitations to widespread biomarker use, including the need for biomarker-guided prospective studies to establish evidence of clinical utility of these new assays.
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Affiliation(s)
- Scott G Westphal
- Division of Nephrology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska; Medical Service, Nebraska Western Iowa Veterans Affairs Health Care System, Omaha, Nebraska
| | - Roslyn B Mannon
- Medical Service, Nebraska Western Iowa Veterans Affairs Health Care System, Omaha, Nebraska.
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Gupta G, Athreya A, Kataria A. Biomarkers in Kidney Transplantation: A Rapidly Evolving Landscape. Transplantation 2025; 109:418-427. [PMID: 39020463 DOI: 10.1097/tp.0000000000005122] [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: 07/19/2024]
Abstract
The last decade has seen an explosion in clinical research focusing on the use of noninvasive biomarkers in kidney transplantation. Much of the published literature focuses on donor-derived cell-free DNA (dd-cfDNA). Although initially studied as a noninvasive means of identifying acute rejection, it is now clear that dd-cfDNA is more appropriately described as a marker of severe injury and irrespective of the etiology, elevated dd-cfDNA ≥0.5% portends worse graft outcomes. Blood gene expression profiling is also commercially available and has mostly been studied in the context of early identification of subclinical rejection, although additional data is needed to validate these findings. Torque teno virus, a ubiquitous DNA virus, has emerged as a biomarker of immunosuppression exposure as peripheral blood Torque teno virus copy numbers might mirror the intensity of host immunosuppression. Urinary chemokine tests including C-X-C motif chemokine ligand 9 and C-X-C motif chemokine ligand 10 have recently been assessed in large clinical trials and hold promising potential for early diagnosis of both subclinical and acute rejection, as well as, for long-term prognosis. Urinary cellular messenger RNA and exosome vesicular RNA based studies require additional validation. Although current data does not lend itself to conclusion, future studies on multimodality testing may reveal the utility of serial surveillance for individualization of immunosuppression and identify windows of opportunity to intervene early and before the irreversible allograft injury sets in.
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Affiliation(s)
- Gaurav Gupta
- Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Akshay Athreya
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Ashish Kataria
- Division of Nephrology, Medical College of Georgia, Augusta, GA
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Bruschi M, Granata S, Leone F, Barberio L, Candiano G, Pontrelli P, Petretto A, Bartolucci M, Spinelli S, Gesualdo L, Zaza G. Omics data integration analysis identified new biological insights into chronic antibody-mediated rejection (CAMR). J Transl Med 2025; 23:209. [PMID: 39979925 PMCID: PMC11844005 DOI: 10.1186/s12967-025-06203-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 02/03/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND In the last two decades, many studies based on omics technologies have contributed to defining the clinical, immunological, and histological fingerprints of chronic antibody-mediated rejection (CAMR), the leading cause of long-term kidney allograft failure. However, the full biological machinery underlying CAMR has only been partially defined, likely due to the fact thatsingle-omics technologies capture only specific aspects of the biological system and fail to provide a comprehensive understanding of this clinical complication. METHODS This study integrated mass spectrometry-based proteomic profiling of serum samples from 19 patients with clinical and histological evidence of CAMR and 26 kidney transplant recipients with normal graft function and histology (CTR) with transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from an independent cohort of 10 CAMR and 8 CTR patients. Data analysis was conducted using unsupervised hierarchical clustering (multidimensional scaling with k-means) and Spearman's correlation test. Partial least squares discriminant analysis (PLS-DA) with the importance in projection (VIP) score identified key proteins differentiating CAMR from CTR. ELISA was used to validate the omics results. RESULTS Proteomic analysis identified 18 proteins that significantly differentiated CAMR from CTR (p < 0.01): five were more abundant (CHI3L1, LYZ, PRSS2, CPQ, IGLV3-32), while 13 were less abundant (SERPINA5, SERPING1, KNG1, CAMP, VNN1, BTD, WDR1, PON3, AHNAK2, MELTF, CA1, CD44, CUL1). Transcriptomic profiling revealed 6 downregulated and 33 upregulated genes in CAMR versus CTR (p < 0.01). Notably, only 2 biological elements were significantly deregulated in both omics analyses: chitinase-3-like protein 1 (CHI3L1) and plasma protease inhibitor C1 (SERPING1). CHI3L1, previously associated with the severity of tissue damage in kidney diseases, was up-regulated in CAMR in both transcriptomics and proteomics, while SERPING1, a serine esterase inhibitor that blocks the classical and lectin pathway of complement, was up-regulated in CAMR in transcriptomics but down-regulated in proteomics. ELISA validated the omics results, and the ROC curve showed that CHI3L1 has good discrimination power between CAMR and CTR (AUC of ROC curve of 0.81). CONCLUSIONS Our multi-omics data, although performed in a relatively small cohort of patients, revealed new systemic biological elements involved in the pathogenesis of CAMR and identified CHI3L1 as a new potential biomarker and/or therapeutic target for this important clinical complication. Future validation of these findings in larger patient cohorts should be conducted to better evaluate their clinical utility.
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Affiliation(s)
- Maurizio Bruschi
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
| | - Simona Granata
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036, Rende, Italy
| | - Francesca Leone
- Division of Nephrology, Dialysis and Transplantation, Annunziata Hospital, Cosenza, Italy
| | - Laura Barberio
- Department of Biology, Ecology and Earth Sciences, University of Calabria, 87036, Rende, Italy
| | - Giovanni Candiano
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Andrea Petretto
- Proteomics and Clinical Metabolomics Unit at the Core Facilities, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy
| | - Martina Bartolucci
- Proteomics and Clinical Metabolomics Unit at the Core Facilities, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy
| | - Sonia Spinelli
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari Aldo Moro, Bari, Italy
| | - Gianluigi Zaza
- Division of Nephrology, Dialysis and Transplantation, Annunziata Hospital, Cosenza, Italy.
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy.
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Masset C, Danger R, Degauque N, Dantal J, Giral M, Brouard S. Blood Gene Signature as a Biomarker for Subclinical Kidney Allograft Rejection: Where Are We? Transplantation 2025; 109:249-258. [PMID: 38867352 DOI: 10.1097/tp.0000000000005105] [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: 06/14/2024]
Abstract
The observation decades ago that inflammatory injuries because of an alloimmune response might be present even in the absence of concomitant clinical impairment in allograft function conduced to the later definition of subclinical rejection. Many studies have investigated the different subclinical rejections defined according to the Banff classification (subclinical T cell-mediated rejection and antibody-mediated rejection), overall concluding that these episodes worsened long-term allograft function and survival. These observations led several transplant teams to perform systematic protocolar biopsies to anticipate treatment of rejection episodes and possibly prevent allograft loss. Paradoxically, the invasive characteristics and associated logistics of such procedures paved the way to investigate noninvasive biomarkers (urine and blood) of subclinical rejection. Among them, several research teams proposed a blood gene signature developed from cohort studies, most of which achieved excellent predictive values for the occurrence of subclinical rejection, mainly antibody-mediated rejection. Interestingly, although all identified genes relate to immune subsets and pathways involved in rejection pathophysiology, very few transcripts are shared among these sets of genes, highlighting the heterogenicity of such episodes and the difficult but mandatory need for external validation of such tools. Beyond this, their application and value in clinical practice remain to be definitively demonstrated in both biopsy avoidance and prevention of clinical rejection episodes. Their combination with other biomarkers, either epidemiological or biological, could contribute to a more accurate picture of a patient's risk of rejection and guide clinicians in the follow-up of kidney transplant recipients.
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Affiliation(s)
- Christophe Masset
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Richard Danger
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Nicolas Degauque
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Jacques Dantal
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Magali Giral
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
| | - Sophie Brouard
- Institut de Transplantation-Urologie-Néphrologie (ITUN), Nantes University Hospital, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, Nantes, France
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Jin C, Xue L, Zhang L, Yu L, Wu P, Qian H. Engineered Nanoparticles for Theranostic Applications in Kidney Repair. Adv Healthc Mater 2025; 14:e2402480. [PMID: 39617999 DOI: 10.1002/adhm.202402480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 11/05/2024] [Indexed: 01/03/2025]
Abstract
Kidney diseases are characterized by their intricate nature and complexity, posing significant challenges in their treatment and diagnosis. Nanoparticles (NPs), which can be further classified as synthetic and biomimetic NPs, have emerged as promising candidates for treating various diseases. In recent years, the development of engineered nanotherapeutics has focused on targeting damaged tissues and serving as drug delivery vehicles. Additionally, these NPs have shown superior sensitivity and specificity in diagnosis and imaging, thus providing valuable insights for the early detection of diseases. This review aims to focus on the application of engineered synthetic and biomimetic NPs in kidney diseases in the aspects of treatment, diagnosis, and imaging. Notably, the current perspectives and challenges are evaluated, which provide inspiration for future research directions, and encourage the clinical application of NPs in this field.
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Affiliation(s)
- Can Jin
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, 215300, China
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Lingling Xue
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Leilei Zhang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
| | - Lixia Yu
- Department of Nephrology, Affiliated Kunshan Hospital of Jiangsu University, Kunshan, Jiangsu, 215300, China
| | - Peipei Wu
- Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Hui Qian
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China
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11
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Shaman JA. The Future of Pharmacogenomics: Integrating Epigenetics, Nutrigenomics, and Beyond. J Pers Med 2024; 14:1121. [PMID: 39728034 DOI: 10.3390/jpm14121121] [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: 10/28/2024] [Revised: 11/19/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Pharmacogenomics (PGx) has revolutionized personalized medicine by empowering the tailoring of drug treatments based on individual genetic profiles. However, the complexity of drug response mechanisms necessitates the integration of additional biological and environmental factors. This article explores integrating epigenetics, nutrigenomics, microbiomes, protein interactions, exosomes, and metabolomics with PGx to enhance personalized medicine. In addition to discussing these scientific advancements, we examine the regulatory and ethical challenges of translating multi-omics into clinical practice, including considerations of data privacy, regulatory oversight, and equitable access. By framing these factors within the context of Medication Adherence, Medication Appropriateness, and Medication Adverse Events (MA3), we aim to refine therapeutic strategies, improve drug efficacy, and minimize adverse effects, with the goal of improving personalized medicine. This approach has the potential to benefit patients, healthcare providers, payers, and the healthcare system as a whole by enabling more precise and effective treatments.
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12
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Tharmaraj D, Mulley WR, Dendle C. Current and emerging tools for simultaneous assessment of infection and rejection risk in transplantation. Front Immunol 2024; 15:1490472. [PMID: 39660122 PMCID: PMC11628869 DOI: 10.3389/fimmu.2024.1490472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
Infection and rejection are major complications that impact transplant longevity and recipient survival. Balancing their risks is a significant challenge for clinicians. Current strategies aimed at interrogating the degree of immune deficiency or activation and their attendant risks of infection and rejection are imprecise. These include immune (cell counts, function and subsets, immunoglobulin levels) and non-immune (drug levels, viral loads) markers. The shared risk factors between infection and rejection and the bidirectional and intricate relationship between both entities further complicate transplant recipient care and decision-making. Understanding the dynamic changes in the underlying net state of immunity and the overall risk of both complications in parallel is key to optimizing outcomes. The allograft biopsy is the current gold standard for the diagnosis of rejection but is associated with inherent risks that warrant careful consideration. Several biomarkers, in particular, donor derived cell-free-DNA and urinary chemokines (CXCL9 and CXCL10), show significant promise in improving subclinical and clinical rejection risk prediction, which may reduce the need for allograft biopsies in some situations. Integrating conventional and emerging risk assessment tools can help stratify the individual's short- and longer-term infection and rejection risks in parallel. Individuals identified as having a low risk of rejection may tolerate immunosuppression wean to reduce medication-related toxicity. Serial monitoring following immunosuppression reduction or escalation with minimally invasive tools can help mitigate infection and rejection risks and allow for timely diagnosis and treatment of these complications, ultimately improving allograft and patient outcomes.
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Affiliation(s)
- Dhakshayini Tharmaraj
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - William R. Mulley
- Department of Nephrology, Monash Health, Clayton, VIC, Australia
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
| | - Claire Dendle
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, VIC, Australia
- Monash Infectious Diseases, Monash Health, Clayton, VIC, Australia
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13
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Jana K, Rammohan A, Ramani A, Gunasekaran B, Vij M, Ramamoorthi M, Jayakanthan N, Kaliamoorthy I, Ramani A, Rela M. Role of Donor-derived Cell-free DNA In Predicting Short-term Allograft Health In Liver Transplant Recipients. J Clin Exp Hepatol 2024; 14:101477. [PMID: 39170833 PMCID: PMC11334858 DOI: 10.1016/j.jceh.2024.101477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 06/27/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND/AIMS Predicting allograft dysfunction prior to clinical or biochemical evidence remains one of the challenges in transplantation, and a preclinical detection and early management of its cause allows for improved post-transplant outcomes. Donor-derived cell-free DNA (ddcfDNA) has been proposed as an important biomarker of allograft injury and has shown to predict dysfunction prior to any biochemical derangements. We aimed to investigate the diagnostic performance of ddcfDNA in detecting and differentiating the causes of early pre-biochemical detection of graft injury and in predicting the short-term outcomes of graft health using a patented protocol and proprietary set of single-nucleotide polymorphisms. METHODS Blood samples were collected on defined postoperative days (1, 3, 7, and at 3 months) and were analysed through relatively economical patented protocol (Trunome™). Biopsy, biochemical tests, and clinical criteria were analysed between various subgroups. RESULTS Of a total 50 patients, percentage ddcfDNA (%ddcfDNA) levels were significantly elevated in the rejection group (n = 8) as compared to that in the non-rejection group (n = 42; median elevation: 12.8% vs 4.3%, respectively), with a significant correlation (r = 0.92, P < 0.0001). Area under the receiver operating characteristic curve (AUC-ROC) analysis revealed that the %ddcfDNA levels can predict graft health more precisely than the conventional liver function tests (AUC for %ddcfDNA: 0.86; P < 0.001; AUC for aspartate transaminase 0.65, P = 0.08; AUC for alanine transaminase: 0.75, P < 0.01). Moreover, %ddcfDNA levels (with a threshold of >10.2%) on post-operative day 7 accurately predicted short-term (3 months) health status of the graft with 93.33% sensitivity, 94.44% specificity, 87.50% positive predictive value, 97.14% negative predictive value, and 94.12% accuracy. CONCLUSION A single-timepoint ddcfDNA on postoperative day 7 accurately predicts graft health and improves risk stratification in the short-term.
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Affiliation(s)
- Koustav Jana
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
| | - Ashwin Rammohan
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
| | | | | | - Mukul Vij
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
| | | | | | - Ilankumaran Kaliamoorthy
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
| | | | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Dr. Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, India
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14
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Goutaudier V, Danger R, Catar RA, Racapé M, Philippe A, Elias M, Raynaud M, Aubert O, Bouton D, Girardin F, Vicaut É, Yaiche S, Demotes J, Heidecke H, Taupin JL, Randoux-Lebrun C, Zaidan M, Papuchon E, Le Mai H, Nguyen TVH, Moreso F, Berney T, Villard J, Legendre C, Dragun D, Papalois V, Potena L, Giral M, Gourraud PA, Brouard S, Crespo E, Halleck F, Budde K, Bestard O, Loupy A, Lefaucheur C. Evaluation of non-invasive biomarkers of kidney allograft rejection in a prospective multicenter unselected cohort study (EU-TRAIN). Kidney Int 2024; 106:943-960. [PMID: 39197587 DOI: 10.1016/j.kint.2024.07.027] [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: 12/27/2023] [Revised: 06/25/2024] [Accepted: 07/26/2024] [Indexed: 09/01/2024]
Abstract
Non-invasive biomarkers are promising tools for improving kidney allograft rejection monitoring, but their clinical adoption requires more evidence in specifically designed studies. To address this unmet need, we designed the EU-TRAIN study, a large prospective multicentric unselected cohort funded by the European Commission. Here, we included consecutive adult patients who received a kidney allograft in nine European transplant centers between November 2018 and June 2020. We prospectively assessed gene expression levels of 19 blood messenger RNAs, four antibodies targeting non-human leukocyte antigen (HLA) endothelial antigens, together with circulating anti-HLA donor-specific antibodies (DSA). The primary outcome was allograft rejection (antibody-mediated, T cell-mediated, or mixed) in the first year post-transplantation. Overall, 412 patients were included, with 812 biopsies paired with a blood sample. CD4 gene expression was significantly associated with rejection, while circulating anti-HLA DSA had a significant association with allograft rejection and a strong association with antibody-mediated rejection. All other tested biomarkers, including AKR1C3, CD3E, CD40, CD8A, CD9, CTLA4, ENTPD1, FOXP3, GZMB, ID3, IL7R, MS4A1, MZB1, POU2AF1, POU2F1, TCL1A, TLR4, and TRIB1, as well as antibodies against angiotensin II type 1 receptor, endothelin 1 type A receptor, C3a and C5a receptors, did not show significant associations with allograft rejection. The blood messenger RNAs and non-HLA antibodies did not show an additional value beyond standard of care monitoring parameters and circulating anti-HLA DSA to predict allograft rejection in the first year post-transplantation. Thus, our results open avenues for specifically designed studies to demonstrate the clinical relevance and implementation of other candidate non-invasive biomarkers in kidney transplantation practice.
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Affiliation(s)
- Valentin Goutaudier
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Richard Danger
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Rusan Ali Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Maud Racapé
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Aurélie Philippe
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany; BIH Biomedical Innovation Academy, Berlin Institute of Health at Charité-Universitätsmedizin Berlin (BIH), Berlin, Germany
| | - Michelle Elias
- Department of Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Marc Raynaud
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France
| | - Olivier Aubert
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Didier Bouton
- DRCI Direction of Clinical Research and Innovation, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - François Girardin
- Division of Clinical Pharmacology, Department of Medicine and Department of Laboratory Medicine and Pathology, Lausanne University Hospital, Faculty of Medicine, University of Lausanne, Lausanne, Switzerland
| | - Éric Vicaut
- Clinical Trial Unit Hospital, Lariboisière Saint-Louis Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Cité University, Paris, France
| | - Sarhan Yaiche
- ECRIN European Clinical Research Infrastructure Network, Paris, France
| | - Jacques Demotes
- ECRIN European Clinical Research Infrastructure Network, Paris, France
| | | | - Jean-Luc Taupin
- Immunology and Histocompatibility Laboratory, Medical Biology Department, Saint-Louis Hospital, Paris, France
| | | | - Mohamad Zaidan
- Department of Nephrology and Transplantation, Kremlin-Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
| | - Emmanuelle Papuchon
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Hoa Le Mai
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Thi-Van-Ha Nguyen
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Francesc Moreso
- Nephrology and Kidney Transplant Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Thierry Berney
- Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Jean Villard
- Department of Immunology and Allergy and Department of Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland
| | - Christophe Legendre
- Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Duska Dragun
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Vassilios Papalois
- European Society for Organ Transplantation (ESOT); Imperial College Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK
| | - Luciano Potena
- European Society for Organ Transplantation (ESOT); Cardiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Magali Giral
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Pierre-Antoine Gourraud
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France; Nantes Université, Centre Hospitalier Universitaire (CHU) Nantes, Pôle Hospitalo-Universitaire 11: Santé Publique, Clinique des données, INSERM, Centre d'Investigation Clinique (CIC) 1413, Nantes, France
| | - Sophie Brouard
- Centre Hospitalier Universitaire (CHU) Nantes, Nantes University, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France; Centre d'Investigation Clinique en Biothérapie, Centre de Ressources Biologiques (CRB), Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - Elena Crespo
- Translational Nephrology and Kidney Transplant Research Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Fabian Halleck
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany
| | - Oriol Bestard
- Nephrology and Kidney Transplant Department, Vall d'Hebron University Hospital, Barcelona, Spain; Translational Nephrology and Kidney Transplant Research Laboratory, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain
| | - Alexandre Loupy
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
| | - Carmen Lefaucheur
- Université Paris Cité, INSERM U970, Paris Institute for Transplantation and Organ Regeneration, Paris, France; Department of Kidney Transplantation, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
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15
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Ettenger RB, Seifert ME, Blydt-Hansen T, Briscoe DM, Holman J, Weng PL, Srivastava R, Fleming J, Malekzadeh M, Pearl M. Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices. Pediatr Transplant 2024; 28:e14836. [PMID: 39147695 DOI: 10.1111/petr.14836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024]
Abstract
INTRODUCTION The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION ClinicalTrials.gov: NCT03719339.
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Affiliation(s)
- Robert B Ettenger
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michael E Seifert
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Tom Blydt-Hansen
- Multi-Organ Transplant Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - David M Briscoe
- Division of Nephrology, Department of Pediatrics Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John Holman
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Patricia L Weng
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Rachana Srivastava
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - James Fleming
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Mohammed Malekzadeh
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Meghan Pearl
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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16
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Kataria A, Athreya A, Gupta G. Biomarkers in Kidney Transplantation. ADVANCES IN KIDNEY DISEASE AND HEALTH 2024; 31:427-435. [PMID: 39232613 DOI: 10.1053/j.akdh.2024.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 06/11/2024] [Indexed: 09/06/2024]
Abstract
Currently in the United States, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. Although early post-transplant care is delivered at the transplant center, the increasing number of kidney transplant recipients requires general nephrologists to actively participate in the long-term care of these patients. Serum creatinine and proteinuria are imperfect traditional biomarkers of allograft dysfunction and lag behind subclinical allograft injury. This manuscript reviews the various clinically available biomarkers in the field of kidney transplantation for a general nephrologist with a focus on the utility of donor-derived cell-free DNA, as a marker of early allograft injury. Blood gene expression profiling, initially studied in the context of early identification of subclinical rejection, awaits validation in larger multicentric trials. Urinary cellular messenger ribonucleic acid and chemokine CXCL10 hold promising potential for early diagnosis of both subclinical and acute rejection. Torque tenovirus, a ubiquitous DNA virus is emerging as a biomarker of immunosuppression exposure as peripheral blood torque tenovirus copy numbers might mirror the intensity of host immunosuppression. Although high-quality evidence is still being generated, evidence and recommendations are provided to aid the general nephrologist in implementation of novel biomarkers in their clinical practice.
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Affiliation(s)
| | - Akshay Athreya
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA
| | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA; Hume-Lee Transplant Center, Virginia Commonwealth University, Richmond, VA.
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17
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Buscher K, Rixen R, Schütz P, Van Marck V, Heitplatz B, Gabriels G, Jehn U, Braun DA, Pavenstädt H, Reuter S. Unveiling systemic responses in kidney transplantation: interplay between the allograft transcriptome and serum proteins. Front Immunol 2024; 15:1398000. [PMID: 39081308 PMCID: PMC11286594 DOI: 10.3389/fimmu.2024.1398000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/01/2024] [Indexed: 08/02/2024] Open
Abstract
Immunity, as defined by systems biology, encompasses a holistic response throughout the body, characterized by intricate connections with various tissues and compartments. However, this concept has been rarely explored in kidney transplantation. In this proof-of-concept study, we investigated a direct association between the allograft phenotype and serum protein signatures. Time-matched samples of graft biopsies and blood serum were collected in a heterogeneous cohort of kidney-transplanted patients (n = 15) for bulk RNA sequencing and proteomics, respectively. RNA transcripts exhibit distinct and reproducible, coregulated gene networks with specific functional profiles. We measured 159 serum proteins and investigated correlations with gene expression networks. Two opposing axes-one related to metabolism and the other to inflammation-were identified. They may represent a biological continuum between the allograft and the serum and correlate with allograft function, but not with interstitial fibrosis or proteinuria. For signature validation, we used two independent proteomic data sets (n = 21). Our findings establish a biological link between the allograft transcriptome and the blood serum proteome, highlighting systemic immune effects in kidney transplantation and offering a promising framework for developing allograft-linked biomarkers.
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Affiliation(s)
- Konrad Buscher
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Rebecca Rixen
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Paula Schütz
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Veerle Van Marck
- Institute of Pathology, University Hospital of Münster, Münster, Germany
| | - Barbara Heitplatz
- Institute of Pathology, University Hospital of Münster, Münster, Germany
| | - Gert Gabriels
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Ulrich Jehn
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Daniela Anne Braun
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Hermann Pavenstädt
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Stefan Reuter
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
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18
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Rroji M, Figurek A, Spasovski G. Advancing kidney transplant outcomes: the role of urinary proteomics in graft function monitoring and rejection detection. Expert Rev Proteomics 2024; 21:297-316. [PMID: 39133121 DOI: 10.1080/14789450.2024.2389829] [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: 03/20/2024] [Revised: 06/15/2024] [Accepted: 07/30/2024] [Indexed: 08/13/2024]
Abstract
INTRODUCTION Kidney transplantation significantly improves the lives of those with end-stage kidney disease, offering best alternative to dialysis. However, transplant success is threatened by the acute and chronic rejection mechanisms due to complex immune responses against the new organ. AREAS COVERED The ongoing research into biomarkers holds promise for revolutionizing the early detection and monitoring of the graft health. Liquid biopsy techniques offer a new avenue, with several diagnostic, predictive, and prognostic biomarkers showing promise in detecting and monitoring kidney diseases and an early and chronic allograft rejection. EXPERT OPINION Evaluating the protein composition related to kidney transplant results could lead to identifying biomarkers that provide insights into the graft functionality. Non-invasive proteomic biomarkers can drastically enhance clinical outcomes and change the way how kidney transplants are evaluated for patients and physicians if they succeed in this transition. Hence, the advancement in proteomic technologies, leads toward a significant improvement in understanding of the protein markers and molecular mechanisms linked to the outcomes of kidney transplants. However, the road from discovery to the use of such proteins in clinical practice is long, with a need for continuous validation and beyond the singular research team with comprehensive infrastructure and across research groups collaboration.
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Affiliation(s)
- Merita Rroji
- Faculty of Medicine, University Department of Nephrology, University of Medicine Tirana, Tirana, Albania
| | - Andreja Figurek
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
| | - Goce Spasovski
- Medical Faculty, University Department of Nephrology, University of Skopje, Skopje, Macedonia
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19
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Falahat P, Scheidt U, Pörner D, Schwab S. Recent Insights in Noninvasive Diagnostic for the Assessment of Kidney and Cardiovascular Outcome in Kidney Transplant Recipients. J Clin Med 2024; 13:3778. [PMID: 38999343 PMCID: PMC11242869 DOI: 10.3390/jcm13133778] [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: 06/17/2024] [Revised: 06/25/2024] [Accepted: 06/25/2024] [Indexed: 07/14/2024] Open
Abstract
Kidney transplantation improves quality of life and prolongs survival of patients with end-stage kidney disease. However, kidney transplant recipients present a higher risk for cardiovascular events compared to the general population. Risk assessment for graft failure as well as cardiovascular events is still based on invasive procedures. Biomarkers in blood and urine, but also new diagnostic approaches like genetic or molecular testing, can be useful tools to monitor graft function and to identify patients of high cardiovascular risk. Many biomarkers have been introduced, whereas most of these biomarkers have not been implemented in clinical routine. Here, we discuss recent developments in biomarkers and diagnostic models in kidney transplant recipients. Because many factors impact graft function and cardiovascular risk, it is most likely that no biomarker will meet the highest demands and standards. We advocate to shift focus to the identification of patients benefitting from molecular and genetic testing as well as from analysis of more specific biomarkers instead of finding one biomarker fitting to all patients.
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Affiliation(s)
- Peyman Falahat
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
| | - Uta Scheidt
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
| | - Daniel Pörner
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
| | - Sebastian Schwab
- Department of Internal Medicine I, Nephrology Section, University of Bonn, 53121 Bonn, Germany
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20
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Xu X, Xu L, Wang J, Wen C, Xia J, Zhang Y, Liang Y. Bioinspired cellular membrane-derived vesicles for mRNA delivery. Theranostics 2024; 14:3246-3266. [PMID: 38855184 PMCID: PMC11155408 DOI: 10.7150/thno.93755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 04/15/2024] [Indexed: 06/11/2024] Open
Abstract
The rapid advancement of mRNA as vaccines and therapeutic agents in the biomedical field has sparked hope in the fight against untreatable diseases. Successful clinical application of mRNA therapeutics largely depends on the carriers. Recently, a new and exciting focus has emerged on natural cell-derived vesicles. These nanovesicles offer many functions, including enhanced drug delivery capabilities and immune evasion, thereby presenting a unique and promising platform for the effective and safe delivery of mRNA therapeutics. In this study, we summarize the characteristics and properties of biomimetic delivery systems for mRNA therapeutics. In particular, we discuss the unique features of cellular membrane-derived vesicles (CDVs) and the combination of synthetic nanovesicles with CDVs.
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Affiliation(s)
- Xiao Xu
- Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Limei Xu
- Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Jingzhi Wang
- Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Caining Wen
- Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Jiang Xia
- Department of Chemistry, The Chinese University of Hong Kong, Hong Kong, China
| | - Yuanmin Zhang
- Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- College of Rehabilitation Medicine, Jining Medical University, Jining, China
| | - Yujie Liang
- Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
- College of Rehabilitation Medicine, Jining Medical University, Jining, China
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21
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Thongwitokomarn H, Noppakun K, Chaiwarith R, Chattipakorn SC, Chattipakorn N. Extracellular vesicles as potential diagnostic markers for kidney allograft rejection. Clin Transplant 2024; 38:e15314. [PMID: 38628057 DOI: 10.1111/ctr.15314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/19/2024]
Abstract
Kidney transplantation is a highly effective treatment for end-stage kidney disease. However, allograft rejection remains a significant clinical challenge in kidney transplant patients. Although kidney allograft biopsy is the gold-standard diagnostic method, it is an invasive procedure. Since the current monitoring methods, including screening of serum creatinine and urinary protein, are not of sufficient sensitivity, there is a need for effective post-transplant monitoring to detect allograft rejection at an early stage. Extracellular vesicles are vesicles with a lipid bilayer that originate from different cell types in pathological and physiological conditions. The content of extracellular vesicles reflects the status of cells at the time of their production. This review comprehensively summarizes clinical, in vivo, and in vitro reports that highlight the potential of extracellular vesicles as diagnostic biomarkers for kidney allograft rejection. Clarification would facilitate differentiation between rejection and non-rejection and identification of the mechanisms involved in the allograft rejection. Despite increasing evidence, further research is necessary to establish the clinical utility of extracellular vesicles in the diagnosis and monitoring of allograft rejection in kidney transplant recipients. Using extracellular vesicles as non-invasive biomarkers for diagnosis of kidney allograft rejection could have tremendous benefits in improving patient outcomes and reduce the need for invasive procedures.
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Affiliation(s)
- Harit Thongwitokomarn
- Faculty of Medicine, Department of Internal Medicine, Division of Infectious Disease, Chiang Mai University, Chiang Mai, Thailand
| | - Kajohnsak Noppakun
- Faculty of Medicine, Department of Internal Medicine, Division of Nephrology, Chiang Mai University, Chiang Mai, Thailand
| | - Romanee Chaiwarith
- Faculty of Medicine, Department of Internal Medicine, Division of Infectious Disease, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand
- Faculty of Medicine, Department of Physiology, Cardiac Electrophysiology Unit, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Faculty of Medicine, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand
- Faculty of Medicine, Department of Physiology, Cardiac Electrophysiology Unit, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
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22
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Xue K, Mi B. Engineered Extracellular Vesicles in Chronic Kidney Diseases: A Comprehensive Review. Int J Nanomedicine 2024; 19:2377-2393. [PMID: 38469058 PMCID: PMC10926925 DOI: 10.2147/ijn.s452393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 02/19/2024] [Indexed: 03/13/2024] Open
Abstract
Chronic kidney diseases (CKD) present a formidable global health challenge, characterized by a deficiency of effective treatment options. Extracellular vesicles (EVs), recognized as multifunctional drug delivery systems in biomedicine, have gained accumulative interest. Specifically, engineered EVs have emerged as a promising therapeutic approach for targeted drug delivery, potentially addressing the complexities of CKD management. In this review, we systematically dissect EVs, elucidating their classification, biogenesis, composition, and cargo molecules. Furthermore, we explore techniques for EV engineering and strategies for their precise renal delivery, focusing on cargo loading and transportation, providing a comprehensive perspective. Moreover, this review also discusses and summarizes the diverse therapeutic applications of engineered EVs in CKD, emphasizing their anti-inflammatory, immunomodulatory, renoprotective, and tissue-regenerating effects. It critically evaluates the challenges and limitations in translating EV therapies from laboratory settings to clinical applications, while outlining future prospects and emerging trends.
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Affiliation(s)
- Kaming Xue
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
| | - Bobin Mi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People’s Republic of China
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23
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Ramalhete L, Araújo R, Ferreira A, Calado CRC. Exosomes and microvesicles in kidney transplantation: the long road from trash to gold. Pathology 2024; 56:1-10. [PMID: 38071158 DOI: 10.1016/j.pathol.2023.10.004] [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: 12/21/2022] [Revised: 09/26/2023] [Accepted: 10/19/2023] [Indexed: 01/24/2024]
Abstract
Kidney transplantation significantly enhances the survival rate and quality of life of patients with end-stage kidney disease. The ability to predict post-transplantation rejection events in their early phases can reduce subsequent allograft loss. Therefore, it is critical to identify biomarkers of rejection processes that can be acquired on routine analysis of samples collected by non-invasive or minimally invasive procedures. It is also important to develop new therapeutic strategies that facilitate optimisation of the dose of immunotherapeutic drugs and the induction of allograft immunotolerance. This review explores the challenges and opportunities offered by extracellular vesicles (EVs) present in biofluids in the discovery of biomarkers of rejection processes, as drug carriers and in the induction of immunotolerance. Since EVs are highly complex structures and their composition is affected by the parent cell's metabolic status, the importance of defining standardised methods for isolating and characterising EVs is also discussed. Understanding the major bottlenecks associated with all these areas will promote the further investigation of EVs and their translation into a clinical setting.
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Affiliation(s)
- Luis Ramalhete
- Blood and Transplantation Center of Lisbon, Instituto Português do Sangue e da Transplantação, Alameda das Linhas de Torres, Lisbon, Portugal; NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal; iNOVA4Health - Advancing Precision Medicine, RG11: Reno-Vascular Diseases Group, NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal.
| | - Ruben Araújo
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal
| | - Aníbal Ferreira
- NOVA Medical School, Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisbon, Portugal; Centro Hospitalar Universitário Lisboa Central, Hospital Curry Cabral, Serviço de Nefrologia, NOVA Medical School, Lisbon, Portugal
| | - Cecília R C Calado
- ISEL - Instituto Superior de Engenharia de Lisboa, Instituto Politécnico de Lisboa, R. Conselheiro Emídio Navarro 1, Lisbon, Portugal; CIMOSM - Centro de Investigação em Modelação e Otimização de Sistemas Multifuncionais, Lisbon, Portugal
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24
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McFaul M, Ventura C, Evans S, Dundar H, Rumpler MJ, McCloskey C, Lowe D, Vlassov AV. Urine exosome mRNA-based test for monitoring kidney allograft rejection: Effects of sample transportation and storage, and interference substances. World J Methodol 2023; 13:492-501. [PMID: 38229935 PMCID: PMC10789111 DOI: 10.5662/wjm.v13.i5.492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/07/2023] [Accepted: 10/23/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Exosomes are 30-150 nm nanovesicles with sophisticated nucleic acids cargo, actively secreted by all cells within human body, and found in abundance in all body fluids, including urine. These extracellular vesicles have tremendous potential for next generation diagnostics, theoretically enabling noninvasive assessment of organ and tissue function via liquid biopsy analysis. AIM Recently, feasibility of an exosomal molecular test was demonstrated for post-organ transplant monitoring: Analysis of urine-derived exosomal mRNA cargo allowed early detection of kidney allograft rejection. Here, we further studied urine-derived exosomes and their mRNA content as a highly promising diagnostic modality. This included stability studies of urine samples and exosomal mRNA upon transportation from the point of collection to a centralized testing facility, short-term storage of urine at different conditions upon receipt till the point molecular assay is performed, and effects of various potentially interfering substances on the downstream quantitative polymerase chain reaction (qPCR) assay. METHODS The urine specimens were stored at various conditions and pre-processed in different ways. Next, samples were passed through the columns to capture all extracellular vesicles, the vesicles were lysed to release their content and the exosomal RNA was purified on the mini-columns, reverse transcription was performed, next pre-amplification, followed by a qPCR analysis for a panel of mRNA markers. RESULTS To ensure exosomal RNA integrity, the harvested urine specimens should be shipped refrigerated, by overnight delivery. Urine can next be stored at the test site for up to 1 wk at 4 °C, and long term should be frozen at -80 °C. Urine specimens must be centrifuge at low G-force to deplete cells and debris, to ensure consistent top results in downstream molecular assays. All commonly used medications (tacrolimus, cyclosporin A, mycophenolic acid, everolimus, sirolimus, ascomycin, teriflunomide) were tested and confirmed that they do not cause assay interference. CONCLUSION mRNA from urine-derived exosomes was shown to be stable across a broad range of conditions and produced accurate results when analyzed via qPCR assay for detection of kidney allograft rejection. We identified the most optimal conditions for every step of the process, ensuring pre-analytical sample integrity and robust qPCR results.
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Affiliation(s)
- Matt McFaul
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Chris Ventura
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Sean Evans
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Halil Dundar
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Marc J Rumpler
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Christopher McCloskey
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Dave Lowe
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
| | - Alexandre V Vlassov
- Department of Research and Development, Thermo Fisher Scientific, West Hills, CA 91304, United States
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25
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Abinti M, Favi E, Alfieri CM, Zanoni F, Armelloni S, Ferraresso M, Cantaluppi V, Castellano G. Update on current and potential application of extracellular vesicles in kidney transplantation. Am J Transplant 2023; 23:1673-1693. [PMID: 37517555 DOI: 10.1016/j.ajt.2023.07.010] [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: 05/02/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/01/2023]
Abstract
Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.
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Affiliation(s)
- Matteo Abinti
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Evaldo Favi
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Carlo Maria Alfieri
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Francesca Zanoni
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA
| | - Silvia Armelloni
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Mariano Ferraresso
- Kidney Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Vincenzo Cantaluppi
- Nephrology and Kidney Transplant Unit, Department of Translational Medicine (DIMET), University of Piemonte Orientale (UPO), "Maggiore della Carita" University Hospital, Novara, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
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26
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Ghodasara A, Raza A, Wolfram J, Salomon C, Popat A. Clinical Translation of Extracellular Vesicles. Adv Healthc Mater 2023; 12:e2301010. [PMID: 37421185 DOI: 10.1002/adhm.202301010] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/03/2023] [Indexed: 07/10/2023]
Abstract
Extracellular vesicles (EVs) occur in a variety of bodily fluids and have gained recent attraction as natural materials due to their bioactive surfaces, internal cargo, and role in intercellular communication. EVs contain various biomolecules, including surface and cytoplasmic proteins; and nucleic acids that are often representative of the originating cells. EVs can transfer content to other cells, a process that is thought to be important for several biological processes, including immune responses, oncogenesis, and angiogenesis. An increased understanding of the underlying mechanisms of EV biogenesis, composition, and function has led to an exponential increase in preclinical and clinical assessment of EVs for biomedical applications, such as diagnostics and drug delivery. Bacterium-derived EV vaccines have been in clinical use for decades and a few EV-based diagnostic assays regulated under Clinical Laboratory Improvement Amendments have been approved for use in single laboratories. Though, EV-based products are yet to receive widespread clinical approval from national regulatory agencies such as the United States Food and Drug Administration (USFDA) and European Medicine Agency (EMA), many are in late-stage clinical trials. This perspective sheds light on the unique characteristics of EVs, highlighting current clinical trends, emerging applications, challenges and future perspectives of EVs in clinical use.
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Affiliation(s)
- Aayushi Ghodasara
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
| | - Aun Raza
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia
| | - Joy Wolfram
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, 4072, Australia
- The School of Chemical Engineering, The University of Queensland, Brisbane, QLD, 4072, Australia
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA
| | - Carlos Salomon
- Translational Extracellular Vesicles in Obstetrics and Gynae-Oncology Group, The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia
- Department of Research, Postgraduate and Further Education (DIPEC), Falcuty of Health Sciences, University of Alba, Santiago, 8320000, Chile
| | - Amirali Popat
- School of Pharmacy, The University of Queensland, Brisbane, QLD, 4102, Australia
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27
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Madhvapathy SR, Wang JJ, Wang H, Patel M, Chang A, Zheng X, Huang Y, Zhang ZJ, Gallon L, Rogers JA. Implantable bioelectronic systems for early detection of kidney transplant rejection. Science 2023; 381:1105-1112. [PMID: 37676965 DOI: 10.1126/science.adh7726] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 07/19/2023] [Indexed: 09/09/2023]
Abstract
Early-stage organ transplant rejection can be difficult to detect. Percutaneous biopsies occur infrequently and are risky, and measuring biomarker levels in blood can lead to false-negative and -positive outcomes. We developed an implantable bioelectronic system capable of continuous, real-time, long-term monitoring of the local temperature and thermal conductivity of a kidney for detecting inflammatory processes associated with graft rejection, as demonstrated in rat models. The system detects ultradian rhythms, disruption of the circadian cycle, and/or a rise in kidney temperature. These provide warning signs of acute kidney transplant rejection that precede changes in blood serum creatinine/urea nitrogen by 2 to 3 weeks and approximately 3 days for cases of discontinued and absent administration of immunosuppressive therapy, respectively.
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Affiliation(s)
- Surabhi R Madhvapathy
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA 60208
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA 60208
| | - Jiao-Jing Wang
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA 60611
| | - Heling Wang
- Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA 60208
- Department of Civil Engineering, Northwestern University, Evanston, IL, USA 60208
- Laboratory of Flexible Electronics Technology, Tsinghua University, Beijing, 100085 China
| | - Manish Patel
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA 60208
- Department of Intervention Radiology, University of Illinois at Chicago, Chicago, IL, USA 60612
| | - Anthony Chang
- Department of Pathology, University of Chicago, Chicago, IL USA 60637
| | - Xin Zheng
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA 60611
| | - Yonggang Huang
- Department of Mechanical Engineering, Northwestern University, Evanston, IL, USA 60208
- Department of Civil Engineering, Northwestern University, Evanston, IL, USA 60208
| | - Zheng J Zhang
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA 60611
- Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 60611
- Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL, USA 60611
| | - Lorenzo Gallon
- Comprehensive Transplant Center, Northwestern University, Chicago, IL, USA 60611
- Department of Nephrology, Northwestern University, Chicago, IL, USA 60611
| | - John A Rogers
- Department of Materials Science and Engineering, Northwestern University, Evanston, IL, USA 60208
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA 60208
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA 60208
- Department of Neurological Surgery, Northwestern University, Chicago, IL, USA 60611
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28
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Peruzzi L, Deaglio S. Rejection markers in kidney transplantation: do new technologies help children? Pediatr Nephrol 2023; 38:2939-2955. [PMID: 36648536 PMCID: PMC10432336 DOI: 10.1007/s00467-022-05872-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 12/18/2022] [Accepted: 12/19/2022] [Indexed: 01/18/2023]
Abstract
Recent insights in allorecognition and graft rejection mechanisms revealed a more complex picture than originally considered, involving multiple pathways of both adaptive and innate immune response, supplied by efficient inflammatory synergies. Current pillars of transplant monitoring are serum creatinine, proteinuria, and drug blood levels, which are considered as traditional markers, due to consolidated experience, low cost, and widespread availability. The most diffuse immunological biomarkers are donor-specific antibodies, which are included in routine post-transplant monitoring in many centers, although with some reproducibility issues and interpretation difficulties. Confirmed abnormalities in these traditional biomarkers raise the suspicion for rejection and guide the indication for graft biopsy, which is still considered the gold standard for rejection monitoring. Rapidly evolving new "omic" technologies have led to the identification of several novel biomarkers, which may change the landscape of transplant monitoring should their potential be confirmed. Among them, urinary chemokines and measurement of cell-free DNA of donor origin are perhaps the most promising. However, at the moment, these approaches remain highly expensive and cost-prohibitive in most settings, with limited clinical applicability; approachable costs upon technology investments would speed their integration. In addition, transcriptomics, metabolomics, proteomics, and the study of blood and urinary extracellular vesicles have the potential for early identification of subclinical rejection with high sensitivity and specificity, good reproducibility, and for gaining predictive value in an affordable cost setting. In the near future, information derived from these new biomarkers is expected to integrate traditional tools in routine use, allowing identification of rejection prior to clinical manifestations and timely therapeutic intervention. This review will discuss traditional, novel, and invasive and non-invasive biomarkers, underlining their strengths, limitations, and present or future applications in children.
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Affiliation(s)
- Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Department, City of Health and Science University Hospital, Piazza Polonia 94, 10126, Turin, Italy.
| | - Silvia Deaglio
- Immunogenetics and Transplant Biology Service, City of Health and Science University Hospital, Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
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29
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Chancharoenthana W, Traitanon O, Leelahavanichkul A, Tasanarong A. Molecular immune monitoring in kidney transplant rejection: a state-of-the-art review. Front Immunol 2023; 14:1206929. [PMID: 37675106 PMCID: PMC10477600 DOI: 10.3389/fimmu.2023.1206929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 07/31/2023] [Indexed: 09/08/2023] Open
Abstract
Although current regimens of immunosuppressive drugs are effective in renal transplant recipients, long-term renal allograft outcomes remain suboptimal. For many years, the diagnosis of renal allograft rejection and of several causes of renal allograft dysfunction, such as chronic subclinical inflammation and infection, was mostly based on renal allograft biopsy, which is not only invasive but also possibly performed too late for proper management. In addition, certain allograft dysfunctions are difficult to differentiate from renal histology due to their similar pathogenesis and immune responses. As such, non-invasive assays and biomarkers may be more beneficial than conventional renal biopsy for enhancing graft survival and optimizing immunosuppressive drug regimens during long-term care. This paper discusses recent biomarker candidates, including donor-derived cell-free DNA, transcriptomics, microRNAs, exosomes (or other extracellular vesicles), urine chemokines, and nucleosomes, that show high potential for clinical use in determining the prognosis of long-term outcomes of kidney transplantation, along with their limitations.
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Affiliation(s)
- Wiwat Chancharoenthana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Tropical Immunology and Translational Research Unit (TITRU), Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Opas Traitanon
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
| | - Asada Leelahavanichkul
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok, Thailand
- Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Adis Tasanarong
- Thammasat Multi-Organ Transplant Center, Thammasat University Hospital, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Thammasat University, Pathumthani, Thailand
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30
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Singh AD, Nagalla B, Patnam S, Satyanaryana G, Andrews R, Panigrahi AK, Mudigonda SS, Maitra S, Rengan AK, Sasidhar MV. Exploring urinary extracellular vesicles for organ transplant monitoring: A comprehensive study for detection of allograft dysfunction using immune-specific markers. Clin Chim Acta 2023; 548:117525. [PMID: 37633321 DOI: 10.1016/j.cca.2023.117525] [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: 05/25/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 08/28/2023]
Abstract
BACKGROUND Allograft dysfunction (AGD) is a common complication following solid organ transplantation (SOT). This study leverages the potential of urinary extracellular vesicles (UEVs) for the non-invasive detection of AGD. AIM We aimed to assess the diagnostic value of T-cell and B-cell markers characteristic of T-cell-mediated and antibody-mediated rejection in UEV-mRNA using renal transplantation as a model. MATERIALS AND METHODS UEVs were isolated from 123 participants, spanning healthy controls, functional transplant recipients, and biopsy-proven AGD patients. T-cell and B-cell marker mRNA expressions were evaluated using RT-qPCR. RESULTS We observed significant differences in marker expression between healthy controls and AGD patients. ROC analysis revealed an AUC of 0.80 for T-cell markers, 0.98 for B-cell markers, and 0.94 for combined markers. T-cell markers achieved 81.3 % sensitivity, 80 % specificity, and 80.4 % efficiency. A triad of T-cell markers (PRF1, OX40, and CD3e) increased sensitivity to 87.5 % and efficiency to 82.1 %. B-cell markers (CD20, CXCL3, CD46, and CF3) delivered 100 % sensitivity and 97.5 % specificity. The combined gene signature of T-cell and B-cell markers offered 93.8 % sensitivity and 95 % specificity. CONCLUSION Our findings underscore the diagnostic potential of UEV-derived mRNA markers for T-cells and B-cells in AGD, suggesting a promising non-invasive strategy for monitoring graft health.
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Affiliation(s)
- Anula Divyash Singh
- Apollo Hospitals Educational and Research Foundation (AHERF), Hyderabad, India; Department of Biomedical Engineering, Indian Institute of Technology Hyderabad (IITH), Kandi, Hyderabad, India
| | - Balakrishna Nagalla
- Apollo Institute of Medical Sciences and Research, Hyderabad, Telangana, Hyderabad, India
| | - Sreekanth Patnam
- Apollo Hospitals Educational and Research Foundation (AHERF), Hyderabad, India; Department of Biomedical Engineering, Indian Institute of Technology Hyderabad (IITH), Kandi, Hyderabad, India
| | - G Satyanaryana
- Department of Nephrology, Apollo Hospitals, Hyderabad, India
| | - Ravi Andrews
- Department of Nephrology, Apollo Hospitals, Hyderabad, India
| | | | | | - Sanjay Maitra
- Department of Nephrology, Apollo Hospitals, Hyderabad, India
| | - Aravind Kumar Rengan
- Department of Biomedical Engineering, Indian Institute of Technology Hyderabad (IITH), Kandi, Hyderabad, India
| | - Manda Venkata Sasidhar
- Apollo Hospitals Educational and Research Foundation (AHERF), Hyderabad, India; Urvogelbio Private Ltd, Hyderabad, India.
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31
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Guo J, Qin C, Li X, Zhuang X. The Flow Cytometric Analysis of Peripheral Blood Lymphocytes and Expression of HLA II Molecules in Lymphocyte During Acute Rejection After Renal Transplantation. J Inflamm Res 2023; 16:2607-2613. [PMID: 37360623 PMCID: PMC10289173 DOI: 10.2147/jir.s410341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
Objective To investigate the changes in the proportion of peripheral blood lymphocytes and the expression of HLA II molecules in lymphocytes during acute rejection after renal transplantation. Methods Thirty-five patients who had undergone renal transplantation were selected. Eighteen patients with clinical and pathological confirmed acute rejection were selected as the test group, and twelve patients without clinical acute rejection symptoms were selected as the control group. Flow cytometry analysis was used to determine the proportion of peripheral blood lymphocytes. The mRNA and protein expression of HLA II molecules on peripheral blood lymphocytes were detected using real-time fluorescence quantification and immunoblotting, respectively. Results The proportion of T lymphocytes, B lymphocytes, and CD4CD8 double positive T cells in the Control Group were 67.48% ± 5.35%, 10.82% ± 1.26%, and 0.88% ± 0.06%, respectively, and in the Test Group were 87.52% ± 6.28%, 3.36% ± 0.26%, and 0.34% ± 0.03%, with a significant difference respectively. The mRNA and protein expressions of HLA II molecules of peripheral blood B lymphocytes in the control group were significantly higher that these in the test group. Conclusion The proportion of peripheral blood T lymphocytes, B lymphocytes, CD4CD8 double positive T cells, and the expression of HLA II molecules of peripheral blood lymphocytes can all indicate the occurrence of acute renal transplantation rejection, which were exceedingly useful to clinicians in judging the acute rejection of renal transplantation in the early stages.
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Affiliation(s)
- Jianzhuang Guo
- Department of Clinical Laboratory, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan, Shandong, People’s Republic of China
| | - Chengwei Qin
- Department of Anesthesiology, Shandong Second Provincial General Hospital, Jinan, Shandong, People’s Republic of China
| | - Xiangdong Li
- Department of Clinical Laboratory, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Jinan, Shandong, People’s Republic of China
| | - Xiaoxuan Zhuang
- International Medical College of Chongqing Medical University, Chongqing, People’s Republic of China
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Nassar A, Cashman K, Rao S, Dagher M, O'Brien C, Afif J, Cravedi P, Azzi JR. Liquid biopsy for non-invasive monitoring of patients with kidney transplants. FRONTIERS IN TRANSPLANTATION 2023; 2:1148725. [PMID: 38993899 PMCID: PMC11235308 DOI: 10.3389/frtra.2023.1148725] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/17/2023] [Indexed: 07/13/2024]
Abstract
The current tools for diagnosing and monitoring native kidney diseases as well as allograft rejection in transplant patients are suboptimal. Creatinine and proteinuria are non-specific and poorly sensitive markers of injury. Tissue biopsies are invasive and carry potential complications. In this article, we overview the different techniques of liquid biopsy and discuss their potential to improve patients' kidney health. Several diagnostic, predictive, and prognostic biomarkers have been identified with the ability to detect and monitor the activity of native kidney diseases as well as early and chronic allograft rejection, such as donor-derived cell-free DNA, exosomes, messenger RNA/microsomal RNA, proteomics, and so on. While the results are encouraging, additional research is still needed as no biomarker appears to be perfect for a routine application in clinical practice. Despite promising advancements in biomarkers, the most important issue is the lack of standardized pre-analytical criteria. Large validation studies and uniformed standard operating procedures are required to move the findings from bench to bedside. Establishing consortia such as the Liquid Biopsy Consortium for Kidney Diseases can help expedite the research process, allow large studies to establish standardized procedures, and improve the management and outcomes of kidney diseases and of kidney transplant recipients.
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Affiliation(s)
- Anthony Nassar
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
| | - Katharine Cashman
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
| | - Shreya Rao
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
| | - Maribel Dagher
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
| | - Connor O'Brien
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
| | - John Afif
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
| | - Paolo Cravedi
- Division of Nephrology, Department of Medicine, Translational Transplant Research Center, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jamil R Azzi
- Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Boston, MA, United States
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Seo JW, Lee YH, Tae DH, Kim YG, Moon JY, Jung SW, Kim JS, Hwang HS, Jeong KH, Jeong HY, Lee SY, Chung BH, Kim CD, Park JB, Seok J, Kim YH, Lee SH. Development and validation of urinary exosomal microRNA biomarkers for the diagnosis of acute rejection in kidney transplant recipients. Front Immunol 2023; 14:1190576. [PMID: 37228607 PMCID: PMC10203902 DOI: 10.3389/fimmu.2023.1190576] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 04/27/2023] [Indexed: 05/27/2023] Open
Abstract
Introduction Acute rejection (AR) continues to be a significant obstacle for short- and long-term graft survival in kidney transplant recipients. Herein, we aimed to examine urinary exosomal microRNAs with the objective of identifying novel biomarkers of AR. Materials and methods Candidate microRNAs were selected using NanoString-based urinary exosomal microRNA profiling, meta-analysis of web-based, public microRNA database, and literature review. The expression levels of these selected microRNAs were measured in the urinary exosomes of 108 recipients of the discovery cohort using quantitative real-time polymerase chain reaction (qPCR). Based on the differential microRNA expressions, AR signatures were generated, and their diagnostic powers were determined by assessing the urinary exosomes of 260 recipients in an independent validation cohort. Results We identified 29 urinary exosomal microRNAs as candidate biomarkers of AR, of which 7 microRNAs were differentially expressed in recipients with AR, as confirmed by qPCR analysis. A three-microRNA AR signature, composed of hsa-miR-21-5p, hsa-miR-31-5p, and hsa-miR-4532, could discriminate recipients with AR from those maintaining stable graft function (area under the curve [AUC] = 0.85). This signature exhibited a fair discriminative power in the identification of AR in the validation cohort (AUC = 0.77). Conclusion We have successfully demonstrated that urinary exosomal microRNA signatures may form potential biomarkers for the diagnosis of AR in kidney transplantation recipients.
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Affiliation(s)
- Jung-Woo Seo
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
- Research Laboratory, Medical Science Institute, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
| | - Yu Ho Lee
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Dong Hyun Tae
- School of Electrical Engineering, Korea University, Seoul, Republic of Korea
| | - Yang Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Su Woong Jung
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jin Sug Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hyeon Seok Hwang
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Kyung-Hwan Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hye Yun Jeong
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - So-Young Lee
- Division of Nephrology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Byung Ha Chung
- Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chan-Duck Kim
- Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Seoul, Republic of Korea
| | - Junhee Seok
- School of Electrical Engineering, Korea University, Seoul, Republic of Korea
| | - Yeong Hoon Kim
- Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Sang-Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University, Seoul, Republic of Korea
- Research Laboratory, Medical Science Institute, Kyung Hee University Hospital at Gangdong, Seoul, Republic of Korea
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Saravanan PB, Kalivarathan J, Khan F, Shah R, Levy MF, Kanak MA. Exosomes in transplantation: Role in allograft rejection, diagnostic biomarker, and therapeutic potential. Life Sci 2023; 324:121722. [PMID: 37100379 DOI: 10.1016/j.lfs.2023.121722] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/10/2023] [Accepted: 04/19/2023] [Indexed: 04/28/2023]
Abstract
Exosomes are 50-200 nm-sized extracellular vesicles that are secreted by cells to transfer signals and communicate with other cells. Recent research has revealed that allograft-specific exosomes containing proteins, lipids, and genetic materials are released into circulation post-transplantation which are powerful indicators of graft failure in solid-organ and tissue transplantations. The macromolecular content of exosomes released by the allograft and the immune cells serve as potential biomarkers for assessing the function and the acceptance/rejection status of the transplanted grafts. Identifying these biomarkers could aid in the development of therapeutic strategies to improve graft longevity. Exosomes can be used to deliver therapeutic agonists/antagonists to grafts and prevent rejection. Inducing long-term graft tolerance has been demonstrated in many studies using exosomes from immunomodulatory cells such as immature DCs, T regulatory cells, and MSCs. The use of graft-specific exosomes for targeted drug therapy has the potential to reduce the unwanted side effects of immunosuppressive drugs. Overall, in this review, we have explored the critical role of exosomes in the recognition and cross-presentation of donor organ-specific antigens during allograft rejection. Additionally, we have discussed the potential of exosomes as a biomarker for monitoring graft function and damage, as well as their potential therapeutic applications in mitigating allograft rejection.
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Affiliation(s)
| | - Jagan Kalivarathan
- VCU Hume-Lee Transplant Institute, VCU health system, Richmond, VA, United States of America
| | - Faizaan Khan
- Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
| | - Rashi Shah
- Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
| | - Marlon F Levy
- VCU Hume-Lee Transplant Institute, VCU health system, Richmond, VA, United States of America; Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
| | - Mazhar A Kanak
- VCU Hume-Lee Transplant Institute, VCU health system, Richmond, VA, United States of America; Department of Surgery, School of Medicine, VCU, Richmond, VA, United States of America
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Atlas-Lazar A, Levy-Erez D. Approach to acute kidney injury following paediatric kidney transplant. Curr Opin Pediatr 2023; 35:268-274. [PMID: 36591982 DOI: 10.1097/mop.0000000000001216] [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] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW In a child with evidence of acute kidney injury (AKI) following renal transplantation, it is important to quickly and accurately diagnose the cause to enable timely initiation of therapeutic interventions. The following article will discuss the differential diagnosis of acute graft dysfunction in paediatric kidney transplant recipients. This review will systematically guide the clinician through the common and less common causes and provide updates on current treatments. RECENT FINDINGS In patients with signs of graft dysfunction, rejection is an important cause to consider. Diagnosis of rejection relies on biopsy findings, an invasive and costly technique. Over the past 5 years, there has been a focus on noninvasive methods of diagnosing rejection, including serum and urinary biomarkers. SUMMARY This review discusses the differential diagnosis of acute graft dysfunction following transplant, with a focus on acute rejection, urinary tract infections and common viral causes, prerenal and postrenal causes, nephrotoxic medications, specifically calcineurin inhibitor toxicity, thrombotic microangiopathy and recurrence of the underlying disease. Each condition is discussed in detail, with a focus on clinical clues to the cause, incidence in the paediatric population, workup and treatment.
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Affiliation(s)
| | - Daniella Levy-Erez
- Schneider Children's Medical Center in Israel, Petah Tikva
- Tel Aviv, University School of Medicine, Tel Aviv, Israel
- Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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36
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Extracellular Vesicles: The Future of Diagnosis in Solid Organ Transplantation? Int J Mol Sci 2023; 24:ijms24065102. [PMID: 36982182 PMCID: PMC10048932 DOI: 10.3390/ijms24065102] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/01/2023] [Accepted: 03/03/2023] [Indexed: 03/10/2023] Open
Abstract
Solid organ transplantation (SOT) is a life-saving treatment for end-stage organ failure, but it comes with several challenges, the most important of which is the existing gap between the need for transplants and organ availability. One of the main concerns in this regard is the lack of accurate non-invasive biomarkers to monitor the status of a transplanted organ. Extracellular vesicles (EVs) have recently emerged as a promising source of biomarkers for various diseases. In the context of SOT, EVs have been shown to be involved in the communication between donor and recipient cells and may carry valuable information about the function of an allograft. This has led to an increasing interest in exploring the use of EVs for the preoperative assessment of organs, early postoperative monitoring of graft function, or the diagnosis of rejection, infection, ischemia-reperfusion injury, or drug toxicity. In this review, we summarize recent evidence on the use of EVs as biomarkers for these conditions and discuss their applicability in the clinical setting.
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37
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Saheera S. Multifaceted role of cardiovascular biomarkers. Indian Heart J 2023; 75:91-97. [PMID: 36736458 PMCID: PMC10123438 DOI: 10.1016/j.ihj.2023.01.011] [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: 10/06/2022] [Revised: 01/23/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
Cardiovascular diseases, a global health issue, claim the lives of many every year. Lifestyle changes and genetic predisposition are the key drivers for the development of CVDs. In many of the patients, the disease is detected at the end stage making heart transplantation the only treatment option. Hence every attempt should be made to identify the risk at an early stage and initiate preventive measures to improve the quality of their life. Biomarkers are one of the critical factors that aid in the early diagnosis of CVDs. More specific and highly sensitive biomarkers have been discovered lately and have been employed for prognosis and diagnosis of CVDs. The present review briefs about the various categories of cardiovascular biomarkers with emphasis on novel biomarkers and discusses the biomarkers employed for different purposes in CVDs. The biomarkers have also helped in identifying COVID-19 patients with increased risk for developing cardiovascular complications. Being non-invasive makes biomarkers advantageous over other methods for evaluating the pathophysiological status of CVDs.
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Affiliation(s)
- Sherin Saheera
- Department of Cardiovascular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01655, USA.
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38
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Importance and implications of exosomes in nephrology and urology. Pflugers Arch 2023; 475:153-166. [PMID: 36399151 PMCID: PMC9849294 DOI: 10.1007/s00424-022-02771-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/31/2022] [Accepted: 11/07/2022] [Indexed: 11/19/2022]
Abstract
Exosomes are extracellular vesicles that are formed by two invaginations of the plasma membrane and can be released by all eukaryotic cells. Because of their bioactive contents, including nucleic acids and proteins, exosomes can activate a variety of functions in their recipient cells. Due to the plethora of physiological and pathophysiological functions, exosomes have received a lot of attention from researchers over the past few years. However, there is still no consensus regarding isolation and characterization protocols of exosomes and their subtypes. This heterogeneity poses a lot of methodical challenges but also offers new clinical opportunities simultaneously. So far, exosome-based research is still mostly limited to preclinical experiments and early-stage clinical trials since the translation of experimental findings remains difficult. Exosomes could potentially play an important role as future diagnostic and prognostic agents and might also be part of the development of new treatment strategies. Therefore, they have previously been investigated in a variety of nephrological and urological conditions such as acute kidney injury or prostate cancer.
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Chaddha M, Rai H, Gupta R, Thakral D. Integrated analysis of circulating cell free nucleic acids for cancer genotyping and immune phenotyping of tumor microenvironment. Front Genet 2023; 14:1138625. [PMID: 37091783 PMCID: PMC10117686 DOI: 10.3389/fgene.2023.1138625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 03/15/2023] [Indexed: 04/25/2023] Open
Abstract
The circulating cell-free nucleic acids (ccfNAs) consist of a heterogenous cocktail of both single (ssNA) and double-stranded (dsNA) nucleic acids. These ccfNAs are secreted into the blood circulation by both healthy and malignant cells via various mechanisms including apoptosis, necrosis, and active secretion. The major source of ccfNAs are the cells of hematopoietic system under healthy conditions. These ccfNAs include fragmented circulating cell free DNA (ccfDNA), coding or messenger RNA (mRNA), long non-coding RNA (lncRNA), microRNA (miRNA), and mitochondrial DNA/RNA (mtDNA and mtRNA), that serve as prospective biomarkers in assessment of various clinical conditions. For, e.g., free fetal DNA and RNA migrate into the maternal plasma, whereas circulating tumor DNA (ctDNA) has clinical relevance in diagnostic, prognostic, therapeutic targeting, and disease progression monitoring to improve precision medicine in cancer. The epigenetic modifications of ccfDNA as well as circulating cell-free RNA (ccfRNA) such as miRNA and lncRNA show disease-related variations and hold potential as epigenetic biomarkers. The messenger RNA present in the circulation or the circulating cell free mRNA (ccf-mRNA) and long non-coding RNA (ccf-lncRNA) have gradually become substantial in liquid biopsy by acting as effective biomarkers to assess various aspects of disease diagnosis and prognosis. Conversely, the simultaneous characterization of coding and non-coding RNAs in human biofluids still poses a significant hurdle. Moreover, a comprehensive assessment of ccfRNA that may reflect the tumor microenvironment is being explored. In this review, we focus on the novel approaches for exploring ccfDNA and ccfRNAs, specifically ccf-mRNA as biomarkers in clinical diagnosis and prognosis of cancer. Integrating the detection of circulating tumor DNA (ctDNA) for cancer genotyping in conjunction with ccfRNA both quantitatively and qualitatively, may potentially hold immense promise towards precision medicine. The current challenges and future directions in deciphering the complexity of cancer networks based on the dynamic state of ccfNAs will be discussed.
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Affiliation(s)
| | | | - Ritu Gupta
- *Correspondence: Deepshi Thakral, ; Ritu Gupta,
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Huang E, Mengel M, Clahsen-van Groningen MC, Jackson AM. Diagnostic Potential of Minimally Invasive Biomarkers: A Biopsy-centered Viewpoint From the Banff Minimally Invasive Diagnostics Working Group. Transplantation 2023; 107:45-52. [PMID: 36508645 PMCID: PMC9746335 DOI: 10.1097/tp.0000000000004339] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 07/15/2022] [Accepted: 07/26/2022] [Indexed: 12/14/2022]
Abstract
With recent advances and commercial implementation of minimally invasive biomarkers in kidney transplantation, new strategies for the surveillance of allograft health are emerging. Blood and urine-based biomarkers can be used to detect the presence of rejection, but their applicability as diagnostic tests has not been studied. A Banff working group was recently formed to consider the potential of minimally invasive biomarkers for integration into the Banff classification for kidney allograft pathology. We review the existing data on donor-derived cell-free DNA, blood and urine transcriptomics, urinary protein chemokines, and next-generation diagnostics and conclude that the available data do not support their use as stand-alone diagnostic tests at this point. Future studies assessing their ability to distinguish complex phenotypes, differentiate T cell-mediated rejection from antibody-mediated rejection, and function as an adjunct to histology are needed to elevate these minimally invasive biomarkers from surveillance tests to diagnostic tests.
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Affiliation(s)
- Edmund Huang
- Division of Nephrology, Department of Medicine, Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Michael Mengel
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Marian C. Clahsen-van Groningen
- Department of Pathology and Clinical Bioinformatics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Erasmus MC Transplant Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Institute of Experimental and Systems Biology, RWTH Aachen University, Aachen, Germany
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Tenchov R, Sasso JM, Wang X, Liaw WS, Chen CA, Zhou QA. Exosomes─Nature's Lipid Nanoparticles, a Rising Star in Drug Delivery and Diagnostics. ACS NANO 2022; 16:17802-17846. [PMID: 36354238 PMCID: PMC9706680 DOI: 10.1021/acsnano.2c08774] [Citation(s) in RCA: 259] [Impact Index Per Article: 86.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 10/21/2022] [Indexed: 05/03/2023]
Abstract
Exosomes are a subgroup of nanosized extracellular vesicles enclosed by a lipid bilayer membrane and secreted by most eukaryotic cells. They represent a route of intercellular communication and participate in a wide variety of physiological and pathological processes. The biological roles of exosomes rely on their bioactive cargos, including proteins, nucleic acids, and lipids, which are delivered to target cells. Their distinctive properties─innate stability, low immunogenicity, biocompatibility, and good biomembrane penetration capacity─allow them to function as superior natural nanocarriers for efficient drug delivery. Another notably favorable clinical application of exosomes is in diagnostics. They hold various biomolecules from host cells, which are indicative of pathophysiological conditions; therefore, they are considered vital for biomarker discovery in clinical diagnostics. Here, we use data from the CAS Content Collection and provide a landscape overview of the current state and delineate trends in research advancement on exosome applications in therapeutics and diagnostics across time, geography, composition, cargo loading, and development pipelines. We discuss exosome composition and pathway, from their biogenesis and secretion from host cells to recipient cell uptake. We assess methods for exosome isolation and purification, their clinical applications in therapy and diagnostics, their development pipelines, the exploration goals of the companies, the assortment of diseases they aim to treat, development stages of their research, and publication trends. We hope this review will be useful for understanding the current knowledge in the field of medical applications of exosomes, in an effort to further solve the remaining challenges in fulfilling their potential.
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Affiliation(s)
- Rumiana Tenchov
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Janet M. Sasso
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Xinmei Wang
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Wen-Shing Liaw
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Chun-An Chen
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
| | - Qiongqiong Angela Zhou
- CAS, a Division of the American Chemical
Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United
States
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Liu X, Liu D, Zhou S, Jiang W, Zhang J, Hu J, Liao G, Liao J, Guo Z, Li Y, Yang S, Li S, Chen H, Guo Y, Li M, Fan L, Li L, Zhao M, Liu Y. CARARIME: Interactive web server for comprehensive analysis of renal allograft rejection in immune microenvironment. Front Immunol 2022; 13:1026280. [DOI: 10.3389/fimmu.2022.1026280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/24/2022] [Indexed: 11/18/2022] Open
Abstract
BackgroundRenal transplantation is a very effective treatment for renal failure patients following kidney transplant. However, the clinical benefit is restricted by the high incidence of organ rejection. Therefore, there exists a wealth of literature regarding the mechanism of renal transplant rejection, including a large library of expression data. In recent years, research has shown the immune microenvironment to play an important role in renal transplant rejection. Nephrology web analysis tools currently exist to address chronic nephropathy, renal tumors and children’s kidneys, but no such tool exists that analyses the impact of immune microenvironment in renal transplantation rejection.MethodsTo fill this gap, we have developed a web page analysis tool called Comprehensive Analysis of Renal Allograft Rerejction in Immune Microenvironment (CARARIME).ResultsCARARIME analyzes the gene expression and immune microenvironment of published renal transplant rejection cohorts, including differential analysis (gene expression and immune cells), prognosis analysis (logistics regression, Univariable Cox Regression and Kaplan Meier), correlation analysis, enrichment analysis (GSEA and ssGSEA), and ROC analysis.ConclusionsUsing this tool, researchers can easily analyze the immune microenvironment in the context of renal transplant rejection by clicking on the available options, helping to further the development of approaches to renal transplant rejection in the immune microenvironment field. CARARIME can be found in http://www.cararime.com.
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Kim MJ, Lim SJ, Ko Y, Kwon HE, Jung JH, Kwon H, Go H, Park Y, Kim TK, Jung M, Pack CG, Kim YH, Kim K, Shin S. Urinary Exosomal Cystatin C and Lipopolysaccharide Binding Protein as Biomarkers for Antibody−Mediated Rejection after Kidney Transplantation. Biomedicines 2022; 10:biomedicines10102346. [PMID: 36289608 PMCID: PMC9598834 DOI: 10.3390/biomedicines10102346] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 11/18/2022] Open
Abstract
We aimed to discover and validate urinary exosomal proteins as biomarkers for antibody−mediated rejection (ABMR) after kidney transplantation. Urine and for-cause biopsy samples from kidney transplant recipients were collected and categorized into the discovery cohort (n = 36) and a validation cohort (n = 65). Exosomes were isolated by stepwise ultra-centrifugation for proteomic analysis to discover biomarker candidates for ABMR (n = 12). Of 1820 exosomal proteins in the discovery cohort, four proteins were specifically associated with ABMR: cystatin C (CST3), serum paraoxonase/arylesterase 1, retinol-binding protein 4, and lipopolysaccharide−binding protein (LBP). In the validation cohort, the level of urinary exosomal LBP was significantly higher in the ABMR group (n = 25) compared with the T-cell-mediated rejection (TCMR) group and the no major abnormality (NOMOA) group. Urinary exosomal CST3 level was significantly higher in the ABMR group compared with the control and NOMOA groups. Immunohistochemical staining showed that LBP and CST3 in the glomerulus were more abundant in the ABMR group compared with other groups. The combined prediction probability of urinary exosomal LBP and CST3 was significantly correlated with summed LBP and CST3 intensity scores in the glomerulus and peritubular capillary as well as Banff g + ptc scores. Urinary exosomal CST3 and LBP could be potent biomarkers for ABMR after kidney transplantation.
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Affiliation(s)
- Mi Joung Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Seong Jun Lim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Youngmin Ko
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hye Eun Kwon
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Joo Hee Jung
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Hyunwook Kwon
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Heounjeong Go
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Yangsoon Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Tae-Keun Kim
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - MinKyo Jung
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Chan-Gi Pack
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Young Hoon Kim
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Kyunggon Kim
- Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Correspondence: (K.K.); (S.S.)
| | - Sung Shin
- Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Correspondence: (K.K.); (S.S.)
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Sedej I, Štalekar M, Tušek Žnidarič M, Goričar K, Kojc N, Kogovšek P, Dolžan V, Arnol M, Lenassi M. Extracellular vesicle-bound DNA in urine is indicative of kidney allograft injury. J Extracell Vesicles 2022; 11:e12268. [PMID: 36149031 PMCID: PMC9503341 DOI: 10.1002/jev2.12268] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 07/29/2022] [Accepted: 09/09/2022] [Indexed: 11/11/2022] Open
Abstract
Extracellular vesicle‐bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer‐unrelated research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well‐characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. The SEC‐based method enriched pure EVs from urine of kidney transplant recipients, regardless of the allograft injury. Urinary evDNA represented up to 29.2 ± 8% (mean ± SD) of cell‐free DNA (cfDNA) and correlated with cfDNA in several characteristics but was less fragmented (P < 0.001). Importantly, using DNase treatment and immunogold labelling TEM, we demonstrated that evDNA was bound to the surface of urinary EVs. Normalised evDNA yield (P = 0.042) and evDNA copy number (P = 0.027) significantly differed between patients with normal histology, rejection injury and non‐rejection injury, the later groups having significantly larger uEVs (mean diameter, P = 0.045) and more DNA bound per uEV. ddDNA is detectable in uEV samples of kidney allograft recipients, but its quantity is highly variable. In a proof‐of‐principle study, several evDNA characteristics correlated with clinical and histological parameters (P = 0.040), supporting that the potential of evDNA as a biomarker for kidney allograft injury should be further investigated.
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Affiliation(s)
- Ivana Sedej
- Department of Nephrology, Division of Internal Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.,Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Maja Štalekar
- Department of Biotechnology and Systems Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Magda Tušek Žnidarič
- Department of Biotechnology and Systems Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Katja Goričar
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Nika Kojc
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Polona Kogovšek
- Department of Biotechnology and Systems Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Vita Dolžan
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Miha Arnol
- Department of Nephrology, Division of Internal Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.,Department of Internal Medicine, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Metka Lenassi
- Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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Song Q, Yu H, Han J, Qiang Lv JL, Yang H. Exosomes in urological diseases - Biological functions and clinical applications. Cancer Lett 2022; 544:215809. [PMID: 35777716 DOI: 10.1016/j.canlet.2022.215809] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/02/2022]
Abstract
Exosomes are extracellular vesicles with a variety of biological functions that exist in various biological body fluids and exert their functions through proteins, nucleic acids, lipids, and metabolites. Recent discoveries have revealed the functional and biomarker roles of miRNAs in urological diseases, including benign diseases and malignancies. Exosomes have several uses in the diagnosis, treatment, and monitoring of urological diseases, especially cancer. Proteins and nucleic acids can be used as alternative biomarkers for detecting urological diseases. Additionally, exosomes can be detected in most body fluids, thereby avoiding pathogenesis. More importantly, for urological tumors, exosomes display a higher sensitivity than circulating tumor cells and tumor-derived DNA in body fluid biopsies because of their low immunogenicity and high stability. These advantages have made it a research hotspot in recent years. In this review, we focus on the biological characteristics and functions of exosomes and summarize their advantages and the latest progress in the diagnosis and treatment of urological diseases.
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Affiliation(s)
- Qiang Song
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, PR China
| | - Hao Yu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, PR China
| | - Jie Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, PR China
| | - Jiancheng Lv Qiang Lv
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, PR China.
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, 210029, PR China.
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Lim JH, Chung BH, Lee SH, Jung HY, Choi JY, Cho JH, Park SH, Kim YL, Kim CD. Omics-based biomarkers for diagnosis and prediction of kidney allograft rejection. Korean J Intern Med 2022; 37:520-533. [PMID: 35417937 PMCID: PMC9082440 DOI: 10.3904/kjim.2021.518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 01/11/2022] [Indexed: 11/27/2022] Open
Abstract
Kidney transplantation is the preferred treatment for patients with end-stage kidney disease, because it prolongs survival and improves quality of life. Allograft biopsy is the gold standard for diagnosing allograft rejection. However, it is invasive and reactive, and continuous monitoring is unrealistic. Various biomarkers for diagnosing allograft rejection have been developed over the last two decades based on omics technologies to overcome these limitations. Omics technologies are based on a holistic view of the molecules that constitute an individual. They include genomics, transcriptomics, proteomics, and metabolomics. The omics approach has dramatically accelerated biomarker discovery and enhanced our understanding of multifactorial biological processes in the field of transplantation. However, clinical application of omics-based biomarkers is limited by several issues. First, no large-scale prospective randomized controlled trial has been conducted to compare omics-based biomarkers with traditional biomarkers for rejection. Second, given the variety and complexity of injuries that a kidney allograft may experience, it is likely that no single omics approach will suffice to predict rejection or outcome. Therefore, integrated methods using multiomics technologies are needed. Herein, we introduce omics technologies and review the latest literature on omics biomarkers predictive of allograft rejection in kidney transplant recipients.
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Affiliation(s)
- Jeong-Hoon Lim
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Byung Ha Chung
- Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul,
Korea
| | - Sang-Ho Lee
- Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul,
Korea
| | - Hee-Yeon Jung
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Ji-Young Choi
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Jang-Hee Cho
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Sun-Hee Park
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Yong-Lim Kim
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Chan-Duck Kim
- Department of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu,
Korea
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47
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Baan CC, Boer K. Extracellular Vesicles: Promising Candidates in Transplant Function Monitoring. Transplantation 2022; 106:698-699. [PMID: 33979316 DOI: 10.1097/tp.0000000000003821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Carla C Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
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48
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Wang J, Yue BL, Huang YZ, Lan XY, Liu WJ, Chen H. Exosomal RNAs: Novel Potential Biomarkers for Diseases-A Review. Int J Mol Sci 2022; 23:2461. [PMID: 35269604 PMCID: PMC8910301 DOI: 10.3390/ijms23052461] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 01/25/2023] Open
Abstract
Exosomes are a subset of nano-sized extracellular vesicles originating from endosomes. Exosomes mediate cell-to-cell communication with their cargos, which includes mRNAs, miRNAs, lncRNAs, and circRNAs. Exosomal RNAs have cell specificity and reflect the conditions of their donor cells. Notably, their detection in biofluids can be used as a diagnostic marker for various diseases. Exosomal RNAs are ideal biomarkers because their surrounding membranes confer stability and they are detectable in almost all biofluids, which helps to reduce trauma and avoid invasive examinations. However, knowledge of exosomal biomarkers remains scarce. The present review summarizes the biogenesis, secretion, and uptake of exosomes, the current researches exploring exosomal mRNAs, miRNAs, lncRNAs, and circRNAs as potential biomarkers for the diagnosis of human diseases, as well as recent techniques of exosome isolation.
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Affiliation(s)
- Jian Wang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (J.W.); (Y.-Z.H.); (X.-Y.L.)
| | - Bing-Lin Yue
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu 610225, China;
| | - Yong-Zhen Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (J.W.); (Y.-Z.H.); (X.-Y.L.)
| | - Xian-Yong Lan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (J.W.); (Y.-Z.H.); (X.-Y.L.)
| | - Wu-Jun Liu
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China
| | - Hong Chen
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China; (J.W.); (Y.-Z.H.); (X.-Y.L.)
- College of Animal Science, Xinjiang Agricultural University, Urumqi 830052, China
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49
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Westphal SG, Mannon RB. Emerging biomarkers in kidney transplantation and challenge of clinical implementation. Curr Opin Organ Transplant 2022; 27:15-21. [PMID: 34939960 DOI: 10.1097/mot.0000000000000941] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Despite improvement in short-term outcomes after kidney transplantation, long-term outcomes remain suboptimal. Conventional biomarkers are limited in their ability to reliably identify early immunologic and nonimmunologic injury. Novel biomarkers are needed for noninvasive diagnosis of subclinical injury, prediction of response to treatment, and personalization of the care of kidney transplant recipients. RECENT FINDINGS Recent biotechnological advances have led to the discovery of promising molecular biomarker candidates. However, translating potential biomarkers from bench to clinic is challenging, and many potential biomarkers are abandoned prior to clinical implementation. Despite these challenges, several promising urine, blood, and tissue novel molecular biomarkers have emerged and are approaching incorporation into clinical practice. SUMMARY This article highlights the challenges in adopting biomarker-driven posttransplant management and reviews several promising emerging novel biomarkers that are approaching clinical implementation.
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Affiliation(s)
- Scott G Westphal
- Division of Nephrology, Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA
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50
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Walther CP, Civitello AB, Liao KK, Navaneethan SD. Nephrology Considerations in the Management of Durable and Temporary Mechanical Circulatory Support. KIDNEY360 2022; 3:569-579. [PMID: 35582171 PMCID: PMC9034823 DOI: 10.34067/kid.0003382021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 01/04/2022] [Indexed: 01/10/2023]
Abstract
Durable and temporary mechanical circulatory support (MCS) use is growing for a range of cardiovascular indications. Kidney dysfunction is common in people evaluated for or receiving durable or temporary MCS and portends worse outcomes. This kidney dysfunction can be due to preexisting kidney chronic kidney disease (CKD), acute kidney injury (AKI) related to acute cardiovascular disease necessitating MCS, AKI due to cardiac procedures, and acute and chronic MCS effects and complications. Durable MCS, with implantable continuous flow pumps, is used for long-term support in advanced heart failure refractory to guideline-directed medical and device therapy, either permanently or as a bridge to heart transplantation. Temporary MCS-encompassing in this review intra-aortic balloon pumps (IABP), axial flow pumps, centrifugal flow pumps, and venoarterial ECMO-is used for diverse situations: high-risk percutaneous coronary interventions (PCI), acute decompensated heart failure, cardiogenic shock, and resuscitation after cardiac arrest. The wide adoption of MCS makes it imperative to improve understanding of the effects of MCS on kidney health/function and of kidney health/function on MCS outcomes. The complex structure and functions of the kidney, and the complex health states of individuals receiving MCS, makes investigations in this area challenging, and current knowledge is limited. Fortunately, the increasing nephrology toolbox of noninvasive kidney health/function assessments may enable development and testing of individualized management strategies and therapeutics in the future. We review technology, epidemiology, pathophysiology, clinical considerations, and future directions in MCS and nephrology.
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Affiliation(s)
- Carl P. Walther
- Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Andrew B. Civitello
- Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, Texas,Advanced Heart Failure Center of Excellence, Baylor College of Medicine, Houston, Texas
| | - Kenneth K. Liao
- Division of Cardiothoracic Transplantation and Circulatory Support, Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Sankar D. Navaneethan
- Selzman Institute for Kidney Health, Section of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas,Section of Nephrology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Institute of Clinical and Translational Research, Baylor College of Medicine, Houston, Texas
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