Repurposing existing, approved medications is always a great plan to get therapeutics to patients in need much more rapidly. And for disorders of the kidneys, speed is of the essence. Now, a new study from investigators at the University of Edinburgh has found evidence that existing medicines could help treat a serious condition that can cause the kidneys to stop working suddenly.
Findings from a new study performed in mice and published recently in Science Translational Medicine, through an article titled, “Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice,” found that medicines usually used to treat angina and high blood pressure, prevented much of the long-term damage to the kidney and cardiovascular system caused by acute kidney injury (AKI).
Experts hope the findings will pave the way for improved treatment of AKI—a common illness that occurs in approximately 20% of emergency hospital admissions in the U.K. and up to 35 million hospitalizations in the U.S., according to data collected by the CDC from 2000–2014.
“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,” noted senior study investigator Neeraj Dhuan, MD, PhD, a senior clinical lecturer and honorary consultant nephrologist at the University of Edinburgh’s Centre for Cardiovascular Science. “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 see if the same beneficial effects are seen in our patients.”
The condition is usually caused by other illnesses that reduce blood flow to the kidney or due to toxicity arising from some medicines. AKI must be treated quickly to prevent death. AKI can cause long-lasting damage to the kidneys and the cardiovascular system even if the kidneys recover. Of those who survive an episode of AKI, 30% are left with chronic kidney disease (CKD). The remaining 70% that recover full kidney function are at an almost 30-fold increased risk of developing CKD.
A team from the University of Edinburgh found that patients with AKI had increased blood levels of endothelin—a protein that activates inflammation and causes blood vessels to constrict. Moreover, endothelin levels remained high long after kidney function had recovered.
“An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease,” the authors wrote. “Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a four-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent, and endothelium-independent macrovascular and microvascular dysfunction, and increased circulating inflammatory Ly6Chigh monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation.”
After finding the same increase in endothelin in mice with AKI, experts treated the animals with medicines that block the endothelin system. The medications—commonly used to treat angina and high blood pressure—work by stopping the production of endothelin or shutting off endothelin receptors in cells.
The mice were monitored over four weeks after AKI. Those treated with the endothelin-blocking medicines had lower blood pressure, less inflammation, and reduced scarring in the kidney. In addition, their blood vessels were more relaxed, and kidney function was also improved, compared with untreated mice.
“Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD,” the authors stated in their published work. “Endothelin-A blockade reduced circulating and renal proinflammatory Ly6Chigh monocytes and B cells and promoted the recruitment of anti-inflammatory Ly6Clow monocytes to the kidney. However, blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice.”
The investigators were encouraged by their findings and are looking forward to moving their studies into humans to see if the effects continue to hold up.
“Impaired kidney function that results from acute kidney injury can also increase a person’s chance of developing and dying from heart and circulatory diseases, so it’s vital we find ways to reduce this risk, concluded James Leiper, PhD, associate medical director at the British Heart Foundation, who is not associated with the currently published study. “This promising research suggests that widely available medicines could help tackle acute kidney injury’s impact before it can cause damage and further complications. 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.”