Protecting the endothelial glycocalyx to improve transplant rates and outcomes (2016–2020)
The choreography of cardiac and respiratory function is a miracle of biologic engineering. Even at rest, 5 litres of blood is brought into intimate contact with a similar volume of gas each minute, and yet no fluid escapes. In the kidney, no less a feat occurs, with waste products being efficiently filtered from the same high volume blood flow. It is now known that the omnipotent, but fragile, endothelial glycocalyx (EG) which lines the endothelium shoulders the bulk of the job of ensuring that intravascular molecules and fluids remain just that. The EG also carries out a myriad of other functions reflecting its pivotal position at the nexus between the intra- and extravascular spaces. This knowledge has led to recent paradigm changing studies demonstrating that EG shedding underlies the pathogenesis of acute lung injury (ALI) and diabetic kidney disease. Since ischaemia-reperfusion is the most potent initiator of EG shedding, and since ALI is indistinguishable from the primary graft dysfunction which affects 25% of transplanted lungs, the idea behind this proposal is that EG shedding is a common, but significantly under-recognised event during lung and kidney donation and transplantation, contributing to organ under-utilisation and inferior short- and long-term transplant outcomes. Excitingly, our preliminary data strongly support this hypothesis, setting the stage for the development of novel biomarkers to more accurately predict organ function in the recipient and targeted treatments to restore the EG. The objectives of this grant are to exploit our unique access to a large biobank of stored multi-organ donor blood to extend our findings to a larger cohort of lung, but also renal allograft recipients; and to use porcine and human ex-vivo lung and kidney perfusion technology to develop and test a targeted, EG-restoring, intervention through which marginal organs can be resuscitated.