Renal RNAi Rescue After Battlefield Crush Injury
Abstract
Battlefield crush trauma leads to secondary kidney injury in almost half of patients who experience this type of trauma. Kidney damage and impairment of renal function are caused by the rapid release of toxic degradation products from crushed muscle tissue into the bloodstream. These toxic byproducts of damaged muscle tissue move from the blood to the kidneys and harm previously healthy normal kidneys. Traumatic muscle damage is termed rhabdomyolysis, a medical syndrome that can lead to serious complications, including kidney failure. Impaired kidney function impacts the ability to remove waste from the bloodstream and concentrate urine. This renal syndrome presents as a major medical and scientific complication; morbidity is severe and often exacerbated in those undergoing further treatment for coincident trauma and blood loss in an intensive care setting. Medical response to crush injury is merely supportive in nature. Currently, the best treatment option entails rapid deployment of volume repletion in patients experiencing severe hypovolemia or hypovolemic shock. Early-stage volume repletion is the only supportive measure to prevent kidney injury. However, under battlefield conditions, even the delivery and administration of 1-2 liters of intravenous fluid (e.g., saline solution, buffered Ringer’s lactate, albumin solutions, dextran, gelatin, packed red cells, or blood substitutes) to a soldier experiencing combat trauma is not always possible. Untreated injury can progress to late-stage renal disease, in which kidney function diminishes and leads to renal failure. At this late stage, only renal replacement therapies such as dialysis, hemofiltration, and kidney transplantation are viable options, all of which are associated with a significant reduction in quality of life. Currently, no approved drugs are available to treat this kidney injury. This application addresses the critical need to prevent secondary organ damage arising from battlefield crush injury by providing a potent drug intervention. We propose injectable RNA interference targeting a gene in the kidneys that causes and sustains injury. Proof of concept for our innovative drug approach has been validated in animal models and we now propose to treat renal injury in a model of crush trauma. The novelty of this application involves using RNA interference to specifically treat this injury, which will address a major medical and scientific gap in the current treatment regimen. This innovative research would have a significant impact on the U.S. Armed Forces by equipping military personnel with a drug that can prevent kidney injury after battlefield crush trauma. The development of this RNA interference technology to prevent and treat renal injury has immediate utility and long-term value for our Armed Forces. Crush injury and crush syndrome can result from many combat-related injuries, including the impact trauma caused by structural failure of a vehicle or building after a bombing/explosion. In addition to meeting a medical need of military personnel in harm’s way, these proposed drugs would offer a clear medical and health benefit to the general public. While crush syndrome victims will benefit from this technology, kidney injury is a ubiquitous medical problem associated with poor outcomes, increased risk of chronic renal disease, high rates of mortality, and prolonged hospitalization. Up to 15% of the general population suffer from impaired renal function, with older patients facing the greatest risk of poor outcomes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910547
Entities
People
- Michael Mcdevitt
Organizations
- Sloan-Kettering Institute
- United States Army