Grant: Project Grant

Acute kidney injury (AKI) complicating critical illness is an important problem, contributing to an estimated 1.7 million deaths annually. The burden of AKI care is estimated to cost US1.72 billion per year. Treatment is limited to dialysis which is resource intensive and frequently unavailable in resource-limited settings. Therefore, preventing AKI is a critical step in reducing mortality. Acetaminophen (Tylenol) has the potential to reduce AKI caused by hemoglobin (released from red blood cells) and myoglobin (released from muscle cells). Hemoglobin and myoglobin cause oxidative damage and this is a common mechanism of AKI seen in various conditions including sepsis, malaria and crush injuries. Acetaminophen has been shown to inhibit oxidative stress and reduce kidney dysfunction in pre-clinical models and to reduce hemoglobin-mediated oxidative stress in patients post-cardiac surgery and in patients with sepsis. Our recent randomized controlled trial in adults with severe malaria showed that acetaminophen improved kidney function and reduced the odds of developing AKI. Since children bear the major burden of malaria, it is now crucial to test this protective effect in African children where AKI affects up to 45% of patients. The ultimate goal is to assess the role of acetaminophen as a renoprotective adjunctive therapy in severe malaria. The hypothesis is that acetaminophen will reduce kidney dysfunction by inhibiting hemoglobin-mediated oxidative damage. We propose a randomized controlled trial of adjunctive acetaminophen in African children with severe malaria. If the trial is positive, our results would change management of severe malaria globally. It could be rapidly scalable as acetaminophen is inexpensive, safe and widely used. Our findings will also have broad implications for other major causes of hemoprotein-mediated AKI including crush injury and sepsis, which directly impact thousands of Canadians.