Optimizing Small-Molecule Therapeutics for Diabetic Kidney Disease and Acute Kidney Injury
Abstract
Acute kidney injury (AKI) is serious healthcare problem that is defined as a rapid decline in kidney function due to injury. It occurs in a large number of hospitalized patients; occurs commonly in active military personnel with severe injuries, dehydration, and exertion; and is particularly common in military Veterans, particularly the elderly and those with diabetes. Rather than a single condition, AKI is caused by a spectrum of diseases, but the end results are the same: in severe cases there is kidney failure requiring dialysis, and there is often only partial recovery of kidney function so that many patients will ultimately require lifelong dialysis. Ultimately, AKI accounts for ~$10 billion in US healthcare costs and results in 2 million deaths worldwide annually. Despite being a major healthcare burden, apart from providing patients with dialysis when kidney failure develops, at present no drug treatment has been developed that convincingly reduces the severity of injury or improves recovery of kidney function in patients with AKI. There are a number of reasons for this: (1) most of the new drugs that have been tested in patients with AKI have to be given before or shortly after the injury has occurred despite the fact that most patients, particularly active military personnel with combat-related injuries, are often seen by a physician hours or days after the injury has occurred and (2) because the experimental models that have been used to test new drugs have not been designed to match the types of injury or the types of patients being treated. To address this problem, we develop a drug screening method using zebrafish and mouse models that allowed us to identify a class of small molecules (precursors to drugs) that alter short- and long-term outcomes of AKI when given for short periods of time to animals with established AKI, a number of days after the initiating injury. This represents a significant advance because delayed treatment allows treatment of a large number of patients who present with established AKI at the time of their admission to hospital. Also, treatment for a short period of time with a drug that reduces bad, long-term consequences of AKI would be convenient, as part of a patient’s standard in-patient hospital care, and would be less likely to have cumulative toxicity than the alternative of long-term, continuous treatment to prevent injury progression. The ultimate goal of this proposal therefore is to develop new small molecules that will improve recovery after AKI when given to patients days after injury has occurred and that are effective in multiple experimental models of AKI that reflect the types of AKI and associated diseases, particularly diabetes, that commonly affect combat personnel and Veterans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710610
Entities
People
- Neil A Hukriede
Organizations
- United States Army
- University of Pittsburgh