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Improving the viability of transplanted kidneys using cell therapy


   Department of Molecular Physiology and Cell Signalling

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  Prof P Murray, Dr B Wilm, Prof Marc Clancy  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Transplantation is the gold-standard treatment for end stage kidney disease but there is a shortage of suitable organs. To increase the donor pool, there has been increasing use of so-called ‘marginal’ kidneys from ‘donation after circulatory death’ (DCD) donors which are typically elderly donors with comorbidities. These marginal kidneys are more susceptible to the impacts of ischaemic reperfusion injury (IRI), the sequelae of which is poorer graft function, and higher rates of graft loss. This has prompted the need to identify ways in which kidneys could be reconditioned prior to transplantation, negating the impact of IRI.

Novel kidney perfusion techniques have emerged to facilitate this, particularly normothermic machine perfusion (NMP). NMP provides an experimental model to assess IRI and a unique opportunity to deliver a treatment to the kidney whilst bypassing the systemic circulation. An increasing body of work has been assessing treatments for IRI following renal transplantation using various types of cell therapies. In this programme, we will determine whether a specific cell therapy called adipose-derived regenerative cells (ADRCs) could be a safe and effective treatment for promoting the repair and regeneration of marginal kidneys. These cells are harvested from fat tissue at the bedside and can be administered via the renal artery at the time of transplantation, making the cells a point-of-care therapy. Preliminary data from the Clancy group at the University of Glasgow show that ADRCs can improve renal function and ameliorate IRI following administration in a rat model. These findings led us to our working hypothesis that ADRCs have the potential to improve the health of human kidney transplants.

The overarching aim of this project is to establish the optimal dose and delivery parameters of ADRCs for use in the clinic and assess the immediate effects of the cells on renal function. To this end we will use ex vivo pig kidneys maintained on a NMP device, and we will monitor the behaviour of the administered cells using a novel non-invasive imaging technology called magnetic particle imaging (MPI).

Our group at Liverpool has extensive expertise of tracking cells using non-invasive imaging techniques. We have previously assessed the biodistribution of cells labelled with super-paramagnetic iron oxide nanoparticles (SPIONs) in mouse kidneys by detecting them with magnetic resonance imaging (MRI). While MRI gives excellent anatomical detail of the kidneys, its low sensitivity fails to provide quantitative cell biodistribution data, making it difficult to accurately map the cells within the renal vasculature. Using an emerging technology called MPI, these limitations can be overcome. MPI is an ultra-sensitive, high contrast molecular imaging technique that allows for quantitative detection with no background signal. Liverpool is the first centre in the UK to acquire an MPI (the “Momentum” scanner). Here, we will use MPI to track the SPION-labelled ADRCs within the ex vivo perfused pig kidneys while on NMP. By monitoring the behaviour of the administered ADRCs in real-time, whilst simultaneously assessing their effect on renal function, we will be able to devise the optimal dose and cell delivery parameters, thereby expediting clinical translation.

Specific objectives comprise:

1. Setting up the ex vivo perfused pig kidney system at Liverpool: Pig kidneys are similar in size to human kidneys, so the optimal ADRC dose is expected to be similar in both species. The pig kidneys will be harvested from pigs used in the food industry, which means that no additional pigs will need to be culled for this study.

2. Assessing the effect of ADRC dose on renal health and function: We will measure creatinine clearance, sodium excretion, O2 consumption, lactate and pH over a 6h period after administering a range of doses.

3. Assessing the effect of perfusion parameters on ADRC biodistribution using MPI: After establishing the optimal dose, we will determine the effect of the following parameters on ADRC distribution: temperature; cell concentration; and flow rate at which the cells are delivered.

The project will be supervised by Prof. Patricia Murray and Dr Bettina Wilm (Liverpool) and Prof. Marc Clancy (transplant surgeon, Glasgow).


Funding Notes

This studentship is funded by Kidney Research UK and provides a stipend for 3 years. Tuition fees and consumable costs are also provided. To apply, please send a CV and a cover explaining why you are interested in this project to Patricia Murray. We are planning for the project to start 1st February 2023 though there is some flexibility.

References

1. Harwood R, Bridge J, Ressel L, Scarfe L, Sharkey J, Czanner G, Kalra PA, Odudu A, Kenny S, Wilm B, Murray P (2022). Murine models of renal ischemia reperfusion injury: An opportunity for refinement using noninvasive monitoring methods. Physiological Reports 10(5). doi:10.14814/phy2.15211
2. Amadeo F, Plagge A, Chacko A, Wilm B, Hanson V, Liptrott N, Murray P, Taylor A (2022). Firefly luciferase offers superior performance to AkaLuc for tracking the fate of administered cell therapies. European Journal of Nuclear Medicine and Molecular Imaging https://doi.org/10.1007/s00259-021-05439-4
3. Taylor A, Sharkey S, Harwood R, Scarfe L, Barrow M, Rosseinsky MJ, Adams DJ, Wilm B, Murray P (2019) Multimodal imaging techniques show differences in homing capacity between mesenchymal stromal cells and macrophages in mouse renal injury models. Molecular imaging and biology 22: 904–913 DOI: 10.1007/s11307-019-01458-8
4. Sharkey J, Ressel L, Brillant N, Scarfe L, Wilm B, Park BK, Murray P (2019). A non-invasive imaging toolbox indicates limited therapeutic potential of conditionally activated macrophages in a mouse model of multiple organ dysfunction. Stem Cells International Article ID 7386954, https://doi.org/10.1155/2019/7386954
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