Abstract
Utilization of kidneys from extended criteria donors leads to an increase in average warm ischemia time (WIT), which is associated with larger degrees of ischemia-reperfusion injury (IRI). Kidney resuscitation by extracorporeal perfusion in situ allows up to 60 minutes of asystole after the circulatory death. Molecular studies of kidney grafts from human donors with critically expanded WIT are warranted. Transcriptomes of two human kidneys from two different donors were profiled after 35-45 minutes of WIT and after 120 minutes of normothermic perfusion and compared. Baseline gene expression patterns in ischemic grafts display substantial intrinsic differences. IRI does not lead to substantial change in overall transcription landscape but activates a highly connected protein network with hubs centered on Jun/Fos/ATF transcription factors and HSP1A/HSPA5 heat shock proteins. This response is regulated by positive feedback. IRI networks are enriched in soluble proteins and biofluids assayable substances, thus, indicating feasibility of the longitudinal, minimally invasive assessment in vivo. Mapping of IRI related molecules in ischemic and reperfused kidneys provides a rationale for possible organ conditioning during machine assisted ex vivo normothermic perfusion. A study of natural diversity of the transcriptional landscapes in presumably normal, transplantation-suitable human organs is warranted.
Highlights
Across a variety of transplanted organs, short-term patient and graft outcomes continue to improve [1], with 1-year survival rates for kidney recipients being well over 90% [2, 3]
We showed that reperfusion does not lead to substantial change in overall landscape of kidney transcription but rather activates a specific program resulting in overexpression of highly connected protein network with hubs centered on Jun/Fos/ATF transcription factors and HSP1A/ HSPA5 heat shock proteins
Ischemia-reperfusion injury (IRI) in transplanted organs has been a subject of many studies performed both in animal models [22,23,24] and in human grafts [25], with numerous biomarkers of ischemia-reperfusion injury (IRI) identified in blood, serum, plasma, urine, and kidney biopsies [26, 27]
Summary
Across a variety of transplanted organs, short-term patient and graft outcomes continue to improve [1], with 1-year survival rates for kidney recipients being well over 90% [2, 3]. Improving longer-term outcomes remains a challenge [3]. IRI, which is proportional to donor warm ischemia time (WIT), is one of the main factors influencing kidney graft survival [6]. Recent dramatic increase in the utilization of kidneys from donors after circulatory death and extended criteria donors lead to an increase in average WIT [8, 9]. It is widely accepted that the prevention or the reduction of IRI is imperative to improve graft survival and decrease posttransplant morbidity
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