Developing a Novel Therapy for Rhabdomyolysis
Abstract
We propose a new treatment for a lethal muscle disorder called rhabdomyolysis. Our therapy is expected to greatly reduce the complexity, expense, and provider burden of prolonged field care for injured Warfighters. Explosive blast, burn, and crush injuries frequently cause muscle destruction. Twenty-five percent of Warfighters evacuated to regional centers in recent conflicts suffer from this problem, and the incidence is expected to increase in future conflicts. Destruction of skeletal muscle causes release of a protein called myoglobin into the blood, which causes kidney cell death, leading to kidney failure. A critical kidney function is removal of potassium from the blood in the urine, and severe kidney failure causes buildup of potassium in the blood, stopping the heart. The mortality from un- or undertreated rhabdomyolysis is very high; this occurs in civilians after severe earthquakes and is the second most common cause of death in that setting. Current therapy for rhabdomyolysis requires very large amounts of intravenous fluid (up to 10 liters per patient per day) and often dialysis, and is only supportive while waiting for myoglobin to break down. Both of these supportive measures are difficult to impossible without medical evacuation. Since prolonged field care is expected to become common in future conflicts, it is imperative to develop therapy for rhabdomyolysis that can be provided in the field. Normally, many proteins travel in the blood to the kidney and enter the urine – if we did not retrieve these proteins from the urine and return them to the blood, we would have to make them anew, wasting energy. The kidney has a “recycling” mechanism, a receptor that recognizes “recyclable” proteins in the urine and takes them into kidney cells. This receptor, megalin, is normally helpful, but in rhabdomyolysis it pulls myoglobin into kidney cells, like the Trojans pulled the Greek horse into Troy. If megalin could be turned off before myoglobin entered kidney cells, it would prevent them from dying, preserving the lifesaving function of the kidney; at the same time, myoglobin would stay in the urine and be excreted, removing the threat. We have proved the concept using genetically altered mice in which the gene for megalin can be selectively turned off. When subjected to experimental rhabdomyolysis, normal mice develop severe kidney injury, and some die, while mice with their megalin genetically switched off maintain completely normal kidney function. Fortuitously, an already Food and Drug Administration (FDA)-approved drug, called cilastatin, was recently found to be able to temporarily block the function of megalin in the kidney. We have found that simple cilastatin treatment profoundly protects kidney function from experimental rhabdomyolysis. We propose to develop the essential knowledge required to repurpose this inexpensive, nontoxic drug, cilastatin, to prevent loss of kidney function and death in Warfighters with rhabdomyolysis. Critical questions are: (1) What is the optimal dose and timing for cilastatin administration after injury? (2) Can cilastatin protect the kidneys of large animals subjected to combat-relevant injury? In Aim 1, we will use mice and experimental rhabdomyolysis to determine the optimal dose and timing of cilastatin; test how rhabdomyolysis may be accelerated by conditions common in the military environment, such as volume depletion, caffeine, and ibuprofen use; and then test if modifications to dose or timing are necessary in the presence of these common challenges. In Aim 2, we will give cilastatin to pigs subjected to a well-described model, which includes muscle trauma with rhabdomyolysis and hemorrhage. We will use rigorous methods to determine the extent of renal function after injury, and the extent of protection by cilastatin. Aim 2 experiments will also provide essential data to support an FDA Investigational New Drug application for this new indica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010196
Entities
People
- Michael P. Hutchens
Organizations
- Oregon Health & Science University
- United States Army