Optimizing the delivery of pre-transplantation therapies during normothermic machine perfusion of human kidneys

Despite a severe organ shortage, thousands of kidneys from higher-risk donors go unused each year. These marginal kidneys have an increased susceptibility to ischemia reperfusion injury and the use of these organs may ultimately result in post-transplant complications like graft loss and recipient death. Normothermic machine perfusion has emerged as a platform for ex vivo assessment and repair to increase utilization of higher-risk donor organs without increasing risk to the recipient. This system also allows for the study the pathophysiology of human kidneys exclusively. After developing an understanding of how marginal kidneys behave during periods of controlled perfusion, one can then rationally design pre-transplant therapies to be delivered in isolation on the ex vivo circuit. Through this body of work I have discovered (1) that it is possible to deliver vascular-targeted nanoparticle therapies during normothermic machine perfusion of human kidneys. I have shown that while nanoparticles may accumulate nonspecifically in red cell plugs, I have (2) identified the cause of and cleared the microvascular obstructions within a human kidney using a regimen of tPA and plasminogen. Having re-established microcirculation within a kidney not only improves drug delivery, but also allows for more homogenous oxygen and nutrient delivery, leading to a more viable organ. After having shown that nanoparticles can effectively delivered within this system following tPA and plasminogen treatment, I began to explore which therapeutics to deliver. I have (3) demonstrated that delivering an NLRP3 inhibitor during normothermic machine perfusion helps protect the organ from ischemia reperfusion injury. Finally, I have also (4) developed tools utilizing contrast-enhanced computed tomography to more holistically evaluate the vasculature of the entire kidney when assessing the efficacy of therapeutic approaches. This work almost exclusively utilized human kidneys that were deemed unsuitable for transplantation. Studying the exact specimen I am looking to repair has allowed me to develop highly translational therapeutic approaches that I believe can help improve marginal kidney utilization.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• DiRito, Jenna

Advisor dc:contributor.advisor

• Nicholson, Michael

• kidney
• transplantation
• nanoparticle
• translational
• ischemia reperfusion injury

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/2bc433ea-1310-41de-a5f6-32c873772950/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-8513-5937
0000-0001-7620-0664

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/307976