Extracellular Vesicles are Associated with Human Donor Kidney Characteristics 5 137 of vasodilation through the synthesis and release of vasoactive substances 36, CD31 single-positive EVs might be indicative for kidney quality prior to transplantation. Recently, to aid clinicians in determining kidney quality during NMP, a scoring system has been developed based on the macroscopic appearance and thresholds of renal blood flow and urine output 35. The presence of different EV subsets (such as CD31+ EVs) might be added – after extensive validation in transplanted cohorts – to this scoring system. Potential identification of other EV subsets and their correlation with kidney function post KTx may provide insight into 1) kidney quality, and 2) the specific compartment(s) of the kidney which are injured/functioning sub-optimally before transplantation. However, in the current work, correlation analysis of the other identified EV subsets with donor kidney characteristics or NMP viability markers did not result in any statistically significant correlations; either when analyzed as a group or when examining EV release for each kidney individually. Although K3 and K5 were determined to be of sufficient quality to be transplantable after 6 hours of NMP, we did not observe any trends that differentiated these kidneys from the other ECD kidneys during NMP for any of the markers examined in this study. It must be noted that no direct inferences could be made between kidney quality prior to transplantation (or transplant outcome) and the released EV subsets as none of the kidneys studied were actually transplanted. Additionally, as these kidneys represent ECD kidneys the reported concentrations and observed correlations might be different for non-ECD kidneys. Another limitation of this study is the small sample size: the heterogeneity among the ECD kidneys with respect to e.g., cause of donor death and the type of organ storage might (further) impact the amount and/or subsets of EVs released. However, the observed correlations of different EV subsets with CIT and donor age during the first 60 minutes of NMP do indicate that EV release is related to well-established indicators of kidney quality: both CIT and donor age are known to be detrimental to kidney quality/transplant outcome 4, 37. In conclusion, our findings demonstrate that discarded human ECD kidney grafts release different EV subsets during NMP, and that their release is correlated with well-established indicators of kidney quality such as CIT, donor kidney age, renal blood flow and intrarenal vascular resistance. The identification, quantification and phenotyping of kidney-derived EVs released during NMP may represent a starting point to study the role of EVs as potential biomarkers for kidney graft quality prior to transplantation. How and if the identified (and other) EVs subsets are correlated with kidney function post transplantation will be the focus of future research.
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