Examining the regional physiology of the transplant kidney during normothermic machine perfusion.

Ischaemia-reperfusion injury (IRI) is an unavoidable consequence of deceased-donor kidney transplantation that has a profound effect upon both immediate and long-term graft function. Disruption to microvascular perfusion (MVP) and tissue oxygenation (PtO2) are central to the development of IRI, but detailed regional pathophysiology remains unresolved in the context of renal transplantation. Normothermic machine perfusion (NMP) is a novel preservation technology that aims to improve pre-implantation kidney quality, but may also be used experimentally to investigate transplant reperfusion. My PhD set out to determine the optimal perfusion conditions to improve kidney quality, and to investigate the underlying heterogeneity in pathophysiology within regions of the kidney which may impact kidney quality. Firstly, we used a porcine model of donor kidney retrieval, NMP, and simulated reperfusion to test the hypothesis that reducing current NMP perfusate oxygenation (PPO2) from superoxic levels would improve renal function and reduce reperfusion injury. In kidneys exposed to either short or long cold ischaemic times, reducing PPO2 from the clinical standard to normoxic or hypoxic PPO2 altered oxygen kinetics during NMP but did not influence tubular function, clearance, urine output, or biomarkers of renal injury during simulated reperfusion. Secondly, we used porcine and human models of transplant reperfusion to test the hypothesis that the renal medulla would be disproportionately affected by tissue hypoperfusion, hypoxia and acute inflammation. In a porcine reperfusion series, PtO2 and MVP were significantly altered following IRI when compared to pre-ischaemic baselines, with greater variation and heterogeneity seen in the medulla than in the cortex. In a human reperfusion series, there was widespread initial microcirculatory disruption, persistent lower medullary PtO2 and a distinct medullary inflammatory environment. In summary we have described novel porcine and human renal medullary physiology and inflammation during transplant reperfusion that highlight the need for medulla-specific strategies to ameliorate IRI. We have further determined changes to renal physiology and injury in response to perfusate oxygenation in a novel preservation technology that may guide clinical implementation.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2021

Author dc:creator

• Adams, Thomas David

Advisor dc:contributor.advisor

• Nicholson, michael

• Transplantation
• Ischaemia-Reperfusion Injury
• Kidney
• Medulla
• Microvasculature
• Hypoxia

Licence

• https://www.repository.cam.ac.uk/bitstreams/360867e8-4dcf-46c3-810f-aadaa0f03d31/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.65005

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/317889