Translational and Mechanistic Studies of Hemearginate-mediated Protection of Human Kidney Cells from Injury

Acute kidney injury is a common condition that has no specific therapy except supportive care. Our previous experimental work demonstrated that hemearginate (a drug licensed for human use) upregulated the protective anti-inflammatory enzyme hemeoxygenase-1 and protected aged mice from acute kidney injury. Indeed, our work confirms that aged mice, like aged humans, develop worse kidney injury than young mice following an identical insult. In addition, our recent analysis of approximately 5000 patients that have undergone cardiac surgery at the Royal Infirmary of Edinburgh indicates that acute kidney injury is not only a relatively common complication but is associated with a marked increase in patient mortality.

This project will explore the effect of hemearginate in patients who are at risk of developing acute kidney injury who are about to undergo cardiac surgery. We will also use purified human blood cells from the patients involved in the study and kidney tubular cells to dissect the protective effects of hemearginate upon cells starved of oxygen in cell culture studies as this may yield further novel potential therapies. It is envisaged that this work will lay the foundation for a large UK multi-centre study to test the effects of pre-operative hemearginate administration on the incidence of acute kidney injury and mortality rates in high-risk patients. This could lead to a change in practice and improved patient outcomes in the future.

Acute kidney injury is a common condition that has no specific therapy except supportive care. Following a significant period of preclinical research using experimental murine models of acute kidney injury, we are now developing a translational research programme of relevance to patients and this project will explore the effect of hemearginate in patients about to undergo cardiac surgery. In addition, this project will use purified human blood cells and well validated kidney tubular cells to dissect the protective effects of hemearginate upon cells starved of oxygen in cell culture studies as this may yield further novel potential therapies. The endpoint of this project will establish the safety and efficacy of hemearginate in upregulating the protective anti-inflammatory enzyme hemeoxygenase-1 that has been demonstrated by us and other investigators to effectively limit acute kidney injury. It is envisaged that the legacy of this work will be to lay the foundation for establishing a large UK multi-centre study to test the effects of pre-operative hemearginate administration on the incidence of acute kidney injury and mortality rates in high-risk patients. This could lead to a change in practice and improved patient outcomes in the future.

Beneficiaries would include:

Nephrologists
AKI is a common condition in our clinical practice, and yet therapeutic options are limited. This fellowship would aim to offer evidence of safety and efficacy of a potential preventative treatment for the development of AKI, and improve understanding of the underlying cellular mechanisms. This may offer further novel therapeutic targets for the future.

Cardiothoracic surgeons
HA is a potential preventative measure for one of their major peri-operative complications, reducing morbidity and mortality and improving patient outcomes.

Patients at risk of AKI
The clinical trial is a proof of concept study, which would aim to lay the foundation for establishing a large UK multi-centre study to test the effects of pre-operative HA administration (and consequent HO-1 induction) upon the incidence of AKI and morbidity and mortality rates in high-risk patients undergoing cardiac surgery. This could therefore lead to a change in clinical practice and improve patient outcomes in the future.

NHS management
AKI is a relatively common complication of major surgery and confers an increased risk of mortality and morbidity, leading to prolonged inpatient stays and increased cost. By minimising this risk, there would be marked health economic benefits to reducing the incidence of AKI.

Fellow
This fellowship would offer me experience in conducting a clinical study, which would involve many transferable skills such as those needed to negotiate regulatory and ethical requirements, time management, interpersonal skills (for example consenting patients, liaising with colleagues) as well as statistical analysis. I would hope to gain experience that would allow me to design, conduct, supervise and analyse further clinical studies going forward. This project will also give me experience in basic science, by utilising laboratory techniques that will help further investigate the mechanism of action of HA. These will include basic laboratory techniques such as PCR, western blotting and flow cytometry which will not only improve my skill set but also give me increased knowledge and confidence to critically appraise results and publications.