**4.1 Background**

AKI is the most serious complication of rhabdomyolysis, representing up to 10% of all cases of AKI [4]. Although the exact mechanisms remain unknown, hypovolemia, myoglobinuria, and metabolic acidosis contribute to the pathogenesis of rhabdomyolysis-associated AKI. Importantly, myoglobinuria is likely initiating factor. Myoglobin is a 17.8-kDa iron- and oxygen-binding protein found in the skeletal muscle cells [4]. During rhabdomyolysis, myoglobin is released into the circulation, and since it is freely filtered by the glomerulus, it then enters the tubule epithelial cell through endocytosis. Traditionally, it has been believed that heme and free iron-driven hydroxyl radicals associated with myoglobin contribute to tubular damage through oxidative stress linked mechanisms [30]. Interestingly, it has been suggested recently that myoglobin can also directly promote oxidation of biomolecules, lipid peroxidation, and the generation of isoprostanes through its peroxidase-like enzyme activity [31].

Rhabdomyolysis-associated AKI can be mimicked in murine models through glycerol injection in the hind-leg muscles [27]. In this model, a single bilateral intramuscular injection (7.5mL/kg 50% glycerol) results in development of AKI within 24 hours.
