A team from the University of Edinburgh, in collaboration with Edinburgh’s Royal Infirmary and French researchers, has found that drugs already licensed for use in heart conditions have the potential to treat a serious kidney condition.

A common condition which can lead to chronic kidney disease (CKD) and cause the kidneys to stop working may be treatable with existing medicines, the new study shows.

The Edinburgh-based researchers hope their findings will “pave the way” for improved treatment of acute kidney injury (AKI) and better survival for patients in Scotland and beyond.

Researchers found that medicines normally used to treat angina and high blood pressure can prevent much of the long-term damage caused by AKI to the kidney and cardiovascular system.

Professor James Leiper, Associate Medical Director at the British Heart Foundation (BHF) and Professor of Cardiovascular and Metabolic Health at the University of Glasgow, said it’s vital to find ways to reduce the risk from AKI, which currently accounts for around 20% of emergency hospital admission across the UK:

“This promising research suggests that widely available medicines could help to tackle the impact of acute kidney injury before it can cause damage and further complications.”

Acute kidney injury is usually caused by other illnesses which reduce blood flow to the kidney, or the result of toxicity from certain medicines. If not treated quickly, the condition can lead to death.

The Edinburgh researchers found that patients with an AKI had increased blood levels of endothelin – a protein that triggers inflammation and the constriction of blood vessels, which remained high even after kidney function had recovered.

Among those who survive AKI, 30% are left with CKD, while the 70% who recover full kidney function have a 28 times greater risk of developing CKD in the future. As with CKD progression, patients with AKI were found by the researchers to show increased activation of the endothelin system.

While the molecular pathways involved in the transition from acute kidney injury to CKD are not fully understood, the researchers identified that therapies which intercept this transition will involve blocking the up-regulation of the endothelin system in some way can.

Dr Bean Dhaun, Senior Clinical Lecturer and Honorary Consultant Nephrologist at the University of Edinburgh’s Centre for Cardiovascular Science, said:

“AKI is a harmful condition, particularly in older people and even with recovery it can have a long-term impact on a person’s health.

“Our study shows that blocking the endothelin system prevents the long-term damage of AKI in mice. As these medicines are already available for use in humans, I hope that we can move quickly to seeing if the same beneficial effects are seen in our patients.”

In a mouse study, the researchers first induced AKI and then tested different medicines to effectively block this system.

One such medicine, verapamil – a calcium channel blocker commonly used for high blood pressure and cardiovascular disease – was shown to hold additional benefits in blocking the vasoconstriction that occurs following an AKI and promote vasodilation. Not only did it reduce a rise in blood pressure, but it also protected the kidneys from transitioning to chronic kidney disease.

Another drug tested, an endothelin-A antagonist, was found to provide similar protection by blocking the up-regulation of the renal endothelin system to prevent this transition to CKD.

Both medicines work by stopping the production of endothelin or by shutting off the endothelin receptors in cells.

Timing was essential, with drugs started 24 hours after the initial onset and continued for the 4-week period proving effective in halting the progression to chronic kidney disease. However, when starting 7 days from the initial onset, researchers observed clear damage as the drugs were unable to provide the same protection.

Another key finding is that dual endothelin blockers (endothelin-A/B antagonists) are not effective in providing protection against the consequences of AKI. Selective endothelin-A blockers were able to protect long-term damage and prevent the development of chronic kidney disease.

Compared with untreated mice, the mice that were treated with verapamil or endothelin-A blockers were founded to have improved kidney function and notably lower blood pressure and inflammation as well as reduced kidney scarring.

Commenting on the findings, Professor Leiper, Associate Medical Director at BHF, said:

“While further studies will be needed to demonstrate whether this treatment is safe and effective for patients, this early research is an encouraging first step.”

Although the study only monitored mice over a four-week period, Dr Dhuan explained that endothelin blockers are already proven to be safe for long-term use and future studies for AKI are in the works:

“We are looking at designing a clinical trial in patients with AKI where we might assess the use of endothelin blockers and verapamil.”

He said the current challenge for effectively treating patients with AKIs in Scotland and beyond is that there are no specific treatments that improve longer-term patient outcomes. Additionally, there are not yet standard predictive measures to know which patients will go on to develop longer-term problems following an AKI.

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