Chapter 1 12 The relative stability of EVs (their cargo is protected from fragmentation and degradation by the lipid bilayer 18), and their ubiquitous presence in (relatively) easily obtainable bodily fluids have sparked the interest in EVs as potential biomarkers for disease diagnosis and prognosis 19. As EVs exist at numbers exceeding 1000 particles for each cell of origin, their analysis offers quantitative advantages over less abundant entities such as circulating tumor cells 20, donor-derived cell-free DNA 21, or antibodies against cytoplasmic proteins 22. EVs as potential biomarkers in kidney transplantation Kidney transplantation is the preferred treatment for patients suffering from irreversible, end-stage renal disease - providing increased patient survival over dialysis 23. However, the shortage of available donor kidneys (grafts), the increasing number of patients on the waiting list, and the general aging of the population has led to an increased use of expanded-criteria donor (ECD) grafts as well as grafts procured from donation after circulatory death (DCD) 24 – both of which are associated with poorer transplant outcomes when compared to organs from standard criteria donors 25, 26. An essential problem with the usage of these kidneys is the lack of quality measures needed to guide the clinician in deciding whether to accept or decline the organ. In the past decade, hypothermic machine perfusion (HMP) has gained interest as a promising preservation technique for deceased donor organs 27, showing improved clinical outcomes after kidney transplantation compared with static cold storage 28. The most recent development in organ preservation is normothermic machine perfusion (NMP). In contrast to HMP, NMP aims to restore cellular metabolism and function to the organ, which is achieved through circulation of a warm, oxygenated red blood cell based solution through the organ prior to transplantation 29, 30. Because metabolism is activated, NMP offers the possibility to assess graft status prior to transplantation through monitoring of the perfusion dynamics and analysis of biomarkers (such as EVs) in the perfusion fluids 25, 29, 31, 32. After transplantation - despite potent immunosuppressive therapy - acute rejection of the graft occurs in as much as 21% of transplantations during the first 6 months after transplantation 21. Though the function of kidney allografts are routinely monitored through serum creatinine and urea, and urinary protein concentrations, these markers are relatively insensitive for allograft rejection as a rise in their concentrations does not specifically indicate immunologic rejection
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