Modelling and optimising pretransplant kidney storage

Smith, Thomas Brendan ORCID: 0000-0001-8194-1467 (2020). Modelling and optimising pretransplant kidney storage. University of Birmingham. Ph.D.

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Abstract

When compared to static cold storage (SCS), the hypothermic machine perfusion (HMP) of pretransplant kidneys confers a therapeutic effect to transplant recipients.
The mechanisms conferring this benefit are not fully understood, however are thought to include a metabolic component. The first experiments in this thesis demonstrated that metabolic differences exist between HMP and SCS stored kidneys.
If properly optimised, HMP potentiates further gains for transplant recipients. However, the low throughput of organ storage research reduces the rate new HMP protocols are assessed. Therefore, a novel in vitro model of organ preservation was created. This model permits high-throughput control of fluid shear stress and oxygenation, and both of these environmental stimuli were found to be independent mediators of cellular
survival after simulated preservation. Additionally, oxygen supplementation modulated de novo metabolism in hypothermicly stored proximal tubule cells.
When trialled in whole organ models of HMP, high-dose perfusate oxygenation led to increased cortical concentrations of adenosine triphosphate, and also increased the concentrations of citric acid cycle metabolites produced de novo.
The final chapters of this thesis chart an international collaborative effort to probe the minimal oxygen delivery strategy capable of inducing ex vivo benefit, followed by in vivo validation using animal auto-transplantation models.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):