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Study of Urine Extracellular Vesicles-Derived Protein Biomarkers for the Non-Invasive Monitoring of Kidney-Transplanted Patients

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Study of Urine Extracellular Vesicles-Derived Protein Biomarkers for the Non-Invasive Monitoring of Kidney-Transplanted Patients ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Study of urine extracellular vesicles-derived protein biomarkers for the non-invasive monitoring of kidney- transplanted patients Laura Carreras Planella Doctoral thesis Badalona, 20th October 2020 Thesis directors: Francesc Enric Borràs Serres, PhD Maria Isabel Troya Saborido, PhD 2 PhD programme in Advanced Immunology Department of Cellular Biology, Physiology and Immunology Universitat Autònoma de Barcelona Study of urine extracellular vesicles-derived protein biomarkers for the non-invasive monitoring of kidney-transplanted patients Estudi de biomarcadors proteics derivats de vesícules extracel·lulars de la orina per la monitorització no invasiva de pacients trasplantats de ronyó Thesis presented by Laura Carreras Planella to qualify for the PhD degree in Advanced Immunology by the Universitat Autònoma de Barcelona The presented work has been performed in the ReMAR-IVECAT group at the Germans Trias i Pujol Health Sciences Research Institute (IGTP) under the supervision of Dr. Francesc Enric Borràs Serres, as tutor and co-director, and Dr. Maria Isabel Troya Saborido as co-director. 3 Laura Carreras was sponsored by the Spanish Government with an FPU grant (“Formación de Personal Universitario”, FPU17/01444) and by La Fundació Cellex during the development of the PhD project. This work supported in part by grants from project PI13/ 00050 integrated in the National R+D+I and funded by the ISCIII and the European Regional Development Fund (http://www.isciii.es), the SGR program of Generalitat de Catalunya (2017-SGR-301 REMAR Group), the ISCIII-REDinREN (RD16/0009 Feder Funds), and Fundació Cellex. The project leading to these results has also received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/TR/CI19/52460021. This activity has received funding from the European Institute of Innovation and Technology (EIT), which is supported by the European Union’s Horizon 2020 research and innovation program. The European Patent Application Number 19 383 190.6, related to the use of vitronectin as biomarker for kidney fibrosis, was developed at the Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP). Samples used in this thesis were obtained from a collaboration with the Nephrology Dept. of the Hospital Universitari Germans Trias i Pujol, the Nephrology Dept. of the Hospital Clínic de Barcelona and the Biobank of the Hospital Universitari de Girona Dr. Josep Trueta and Institut d’Investigació Biomèdica de Girona Dr. Josep Trueta. 4 5 TABLE OF CONTENTS Abbreviations ................................................................................................................................... 9 Abstract ............................................................................................................................................ 11 Resum en català ........................................................................................................................... 14 Introduction ................................................................................................................................... 17 1 Brief history of the kidney ............................................................................................. 19 1.1 Brief history of kidney transplantation ......................................................... 25 2 Renal physiology ................................................................................................................ 28 3 Renal failure and kidney transplantation ................................................................ 32 4 Current picture of kidney transplantation epidemiology ................................ 33 5 Graft failure in kidney transplantation ..................................................................... 36 5.1 Interstitial fibrosis and tubular atrophy ........................................................ 38 5.2 CNIT ............................................................................................................................... 40 5.3 Diagnosis, monitoring and histopathological evaluation of the transplanted kidney ............................................................................................................... 42 6 New biomarkers of kidney damage .......................................................................... 48 6.1 Extracellular vesicles .............................................................................................. 49 Hypothesis and objectives ...................................................................................................... 59 1 Hypothesis ............................................................................................................................. 61 2 Objectives .............................................................................................................................. 61 Materials and methods ............................................................................................................. 63 1 Patients and study design ............................................................................................. 65 2 Isolation of EV from urine by size-exclusion chromatography .................... 68 3 determination of uEV-enriched fractions ............................................................... 68 4 Mass-spectrometry proteomics ................................................................................... 70 6 4.1 Discovery proteomics ............................................................................................ 70 4.2 Targeted proteomics .............................................................................................. 71 5 Western Blot ......................................................................................................................... 75 6 Enzyme-linked immunosorbent assay (ELISA) ...................................................... 78 7 Statistical analyses .............................................................................................................. 78 Results ............................................................................................................................................... 81 1 Part I: Proteomic characterization of urinary extracellular vesicles from kidney-transplanted patients treated with calcineurin inhibitors.......................... 83 1.1 Patients and samples collection ....................................................................... 83 1.2 Global analysis of the uEV proteome ............................................................ 88 1.3 Differentially expressed proteins ...................................................................... 90 1.4 Biological processes enrichment analysis .................................................... 93 1.5 Uroplakin expression .............................................................................................. 96 2 Part II: Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts ................................................................................................................................... 97 2.1 Patients and samples collection ....................................................................... 97 2.2 Characterization of uEV-enriched fractions proteome .......................... 98 ......................................................................................................................................................... 99 2.3 Alterations in grafted kidneys are reflected in uEV proteome ....... 100 2.4 Gene set enrichment analysis in IFTA ......................................................... 103 2.5 Differentially expressed proteins in pathological groups .................. 105 2.6 Vitronectin is significantly more expressed in high grade fibrosis samples ..................................................................................................................................... 108 3 Part III: Validation with antibody-based techniques ....................................... 110 3.1 Evaluation of protein biomarkers of renal alterations by WB ......... 110 7 3.2 Validation of vitronectin as biomarker of fibrosis with ELISA ......... 113 Discussion ..................................................................................................................................... 115 1 Part I: Proteomic characterization of urinary extracellular vesicles from kidney-transplanted patients treated with calcineurin inhibitors ....................... 117 2 Part II: Urinary vitronectin identifies patients with high levels of fibrosis in kidney grafts ................................................................................................................................ 122 3 Global Discussion ............................................................................................................
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