Does activation of the endothelin system promote the transition of acute kidney injury to chronic kidney disease?

The kidneys are crucial for normal bodily function. During illness they may suffer and stop working properly. This acute kidney injury (AKI) can require dialysis and even lead to death. Those who survive are at risk of developing chronic kidney disease with its associated increased risk of heart disease. Currently, there are no treatments for AKI and little is known about the processes that cause it to turn into chronic kidney disease.

We have shown that patients with AKI have higher levels of a chemical called endothelin in their blood and urine. Endothelin is a powerful chemical that causes blood vessels to constrict and can also cause inflammation. We propose that high levels of endothelin may contribute to the development of chronic kidney disease after AKI. We have shown in mice that blocking endothelin protects the kidney from chronic kidney disease after acute injury. In this project we will find out why endothelin blocking drugs protect the kidney in mice and examine the endothelin system in 100 people with AKI to see if the system is indeed activated after acute injury. Endothelin-blocking drugs are already available in the clinic and used to treat other diseases. If this project is successful, it will provide evidence to allow us to rapidly test these drugs in humans with AKI.

Acute kidney injury (AKI) is a major health problem. It has a high mortality and is expensive to manage. More recently, it has been recognised that patients surviving AKI have an increased risk of developing chronic kidney disease (CKD) and cardiovascular disease. This risk is further enhanced in the elderly. Our preliminary studies in patients surviving AKI show that they have higher levels of the peptide endothelin-1 in their blood and urine than do healthy controls. We modelled this in mice using 50 minutes of renal ischemia followed by reperfusion to induce AKI. Transient renal ischaemia is the most common cause of AKI in humans; in mice it also caused activation of the endothelin system. We found that chronic kidney damage and inflammation were prevented in mice by treatment with an endothelin receptor antagonist. This project builds on these preliminary studies to find out how endothelin receptor antagonism preserves renal vascular function and reduces inflammation. This study in mice is coupled with a clinical study measuring the activity of the endothelin system in 100 patients across a broad spectrum of AKI. If the outcome of this project is positive, it provides a scientific rationale for a future interventional clinical trial with endothelin receptor blockers, which are already approved for use in humans.

Strategic Importance:

Acute kidney injury (AKI) is common, costly to manage and still carries a high mortality rate. There are no specific treatments. Those who recover from AKI have an increased risk of developing chronic kidney disease (CKD), which also presents a global health burden. In the UK, 3 million people have CKD. For patients and their families, this results in a significant drop in both quality of life and life expectancy. This morbidity is associated with a substantial psychological burden. The economic cost of CKD is high, estimated at ~2% of the annual NHS budget. Current treatment strategies for CKD are limited and this research project addresses a key area of clinical need: identifying a treatment that may reduce the likelihood of developing CKD following AKI. The project has the capability for rapid translation into the clinical arena, providing clear patient, family and societal benefits in accordance with the MRC's mission and strategic objectives.

Our research has the potential to contribute to the nation's health and wealth in a realistic timeframe of 5-10 years by decreasing morbidity, mortality and healthcare costs associated with the AKI-to-CKD transition. This also provides the research community with new understanding of the role of the endothelin system in renal disease, specifically vascular inflammation.

Who benefits and how might they benefit?

1. Patients: The major beneficiaries of our research will be patients. AKI a common condition arising from multiple insults to the kidney. Treatment options are currently supportive. There is limited understanding of the processes that govern the transition from acute injury to chronic disease and our project may ultimately prevent this transition in some patients. rather than halt, progression. 64,000 patients are currently on renal replacement therapy and the need for renal transplant far outstrips the supply. 60,000 people die prematurely in the UK each year because of CKD. Our extensive and robust preliminary data indicate that endothelin antagonists can protect against the development of CKD after AKI. Our project tests this concept in patients and uses an antagonist already shown to be safe and well-tolerated in humans. If successful, our research concept can be rapidly extended to improve patient care.
2. Patients' families: AKI and subsequent progressive CKD has a significant impact on well-being and family/societal roles.
3. Patient representative groups: It is likely that the results of this work will also impact upon local and national patient representative groups who are increasingly concerned about the health and well-being of their members. These groups have already expressed particular interest in working with us to develop new strategies for clinical management of renal patients.
4. Healthcare funders: AKI costs the NHS approximately £500m per year and CKD stages 3 to 5 are estimated to cost the NHS ~£2billion per year. Half this cost is directed toward provision of renal replacement therapy for ~2% of patients. By extending the range of therapeutics to prevent the transition from AKI to CKD our research could curtail costs and consultation rates at primary and secondary care facilities through reducing the morbidity and mortality associated with AKI and ultimately CKD.
5. Researchers: researchers studying AKI specifically and kidney disease in general will benefit from data examining an alternative paradigm where abnormal control of the renal macro- and microvasculature is implicated in disease progression.
6. Broader gains to Industry: through the discovery of new mechanistic disease targets for AKI, this sector could benefit from redeployment opportunities for existing assets and through collaboration with a research group that seamlessly combines preclinical and clinical research.