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Uromodulin: Biomarker for Kidney Tubular Function

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Uromodulin: Biomarker for Kidney Tubular Function Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2017 Uromodulin: biomarker for kidney tubular function Youhanna, Sonia Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-148534 Dissertation Published Version Originally published at: Youhanna, Sonia. Uromodulin: biomarker for kidney tubular function. 2017, University of Zurich, Faculty of Science. Uromodulin: Biomarker for Kidney Tubular Function Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Sonia Youhanna aus dem Libanon Promotionskommission Prof. Dr. Olivier Devuyst (Vorsitz und Leitung der Dissertation) Prof. Dr. Johannes Loffing Prof. Dr. Murielle Bochud Prof. Dr. Olivier Bonny Zürich, 2018 Declaration I hereby declare that this dissertation is the result of my own work and effort. Wherever contributions of others have been involved or other sources of information have been used, they are acknowledged. This work was carried out under the supervision of Prof. Dr. med. Olivier Devuyst at the Institute of Physiology, University of Zurich, Zurich, Switzerland, from November 2011 to December 2016. ii Publications presented in this work: 1- Determination of uromodulin in human urine: influence of storage and processing. Youhanna S., Weber J., Beaujean V., Glaudemans B., Sobek J., Devuyst O. Nephrol Dial Transplant. 2014. 29 (1): 136-145. 2- Common UMOD Variants Influence Urinary and Plasma Levels and Biochemical Properties of Uromodulin Youhanna S., Schaeffer C., Hülsmeier A., Hennet T., Vollenweider P., Köttgen A., Bochud M., Swiss Kidney Project on Genes in Hypertension (SKIPOGH) team, Cohort Lausanne (CoLaus) team, Rampoldi L., Devuyst O. In preparation 3- Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population. Pruijm M., Ponte B., Ackermann D., Paccaud F., Guessous I., Ehret G, Pechère-Bertschi A., Vogt B., Mohaupt MG., Martin PY., Youhanna SC., Nägele N., Vollenweider P., Waeber G., Burnier M., Devuyst O., Bochud M. Clin J Am Soc Nephrol. 2016. 7; 11 (1): 70-80. 4- Clinical, Genetic, and Urinary Factors Associated with Uromodulin Excretion. Troyanov S., Delmas-Frenette C., Bollée G., Youhanna S., Bruat V., Awadalla P., Devuyst O., Madore F. Clin J Am Soc Nephrol. 2016. 7; 11 (1): 62-69. 5- Validation of Surrogates of Urine Osmolality in Population Studies. Youhanna S., Bankir L., Jungers P., Porteous D., Polasek O., Bochud M., Hayward C., Devuyst O. Am J Nephrol. 2017. 46 (1): 26-36. iii Acknowledgements I am very grateful to my supervisor Professor Olivier Devuyst for giving me the chance to acquire the professional knowledge and experience during my thesis. I would like to thank the committee members Prof. Murielle Bochud, Prof. Olivier Bonny and Prof. Johannes Loffing for their interest and their input during the annual committee meetings. I also would like to thank Dr Lise Bankir for hosting me in her lab in Paris and for all the guidance and the support. I am thankful for the IMed program and especially for Mrs Heidi Preisig. I would like to thank all the former and present members of MIKD group for their support, help and good atmosphere. Special thanks go to Rita, Zhongning, Bob, Manuela, Julien, Laurent, Nadine and Jenny. Thank you for the continuous support and for the great memories we had. You made me feel home away from home. My gratitude goes to Manuela and Jenny for their extensive and meticulous proofreading also for translating the abstract. Last but not least, I would like to thank my friends, my parents-in-law, my parents, my brothers, nephews and nieces for their support and love. I am particularly grateful to my sister Grace and my husband Elie for their endless care, love and encouragement. You made everything much easier. iv Table of Contents Acknowledgements .................................................................................................................................... iv Abstract ...................................................................................................................................................... vii Zusammenfassung.................................................................................................................................... viii I. Introduction ............................................................................................................................................. 1 1. Kidney ................................................................................................................................................... 1 1.1 General structure ............................................................................................................................. 1 1.2 Physiology ....................................................................................................................................... 1 1.3 Pathophysiology .............................................................................................................................. 5 2. Biomarkers for renal and tubular function ............................................................................................ 8 2.1 Biomarker: properties and role ....................................................................................................... 8 2.2 Available urinary biomarkers for renal function and disease ......................................................... 9 3. Uromodulin ......................................................................................................................................... 14 3.1 Biology of the protein: Structure and biosynthesis ....................................................................... 14 3.2 Physiology of uromodulin ............................................................................................................. 17 3.3 Pathophysiology of uromodulin .................................................................................................... 21 4. Urine osmolarity ................................................................................................................................. 25 II. Aim of the thesis ................................................................................................................................... 36 III. Determination of Uromodulin in Human Urine: Influence of Storage and Processing ............... 37 Introduction ............................................................................................................................................. 39 Material and Methods ............................................................................................................................. 40 Results ..................................................................................................................................................... 45 Discussion ............................................................................................................................................... 54 IV. Common UMOD Variants Influence Urinary and Plasma Levels and Biochemical Properties of Uromodulin ................................................................................................................................................ 61 Introduction ............................................................................................................................................. 63 Material and Methods ............................................................................................................................. 64 Results ..................................................................................................................................................... 67 Discussion ............................................................................................................................................... 75 V. Uromodulin excretion: Association with clinical and genetic factors in the general population .. 80 Introduction ............................................................................................................................................. 81 Material and Methods ............................................................................................................................. 82 v Results ..................................................................................................................................................... 84 Discussion ............................................................................................................................................... 89 VI. Validation of surrogates of urine osmolality in population studies ............................................... 93 Introduction ............................................................................................................................................. 95 Material and Methods ............................................................................................................................. 96 Results ................................................................................................................................................... 100 Discussion ............................................................................................................................................
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