Improving the viability of transplanted kidneys using cell therapy

Description

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 Murray and Wilm (Liverpool) and Clancy (transplant surgeon, Glasgow).