Mechanism-based therapeutic approaches to rhabdomyolysis-induced renal failure

Abstract

Rhabdomyolysis-induced renal failure represents up to 15% of all cases of acute renal failure. Many studies over the past 4 decades have demonstrated that accumulation of myoglobin in the kidney is central in the mechanism leading to kidney injury. However, some discussion exists regarding the mechanism mediating this oxidant injury. Although the free-iron-catalyzed Fenton reaction has been proposed to explain the tissue injury, more recent evidence strongly suggests that the main cause of oxidant injury is myoglobin redox cycling and generation of oxidized lipids. These molecules can propagate tissue injury and cause renal vasoconstriction, two of the three main conditions associated with acute renal failure. This review presents the evidence supporting the two mechanisms of oxidative injury, describes the central role of myoglobin redox cycling in the pathology of renal failure associated with rhabdomyolysis, and discusses the value of therapeutic interventions aiming at inhibiting myoglobin redox cycling for the treatment of rhabdomyolysis-induced renal failure.

Figure 1. Mechanism for Mb-induced lipid peroxidation and its inhibition by acetaminophen

Oxidation of ferric Mb (Fe(III)Mb) by a lipid hydroperoxide (LOOH) yields the ferryl Mb protoporphyrin radical (Fe(IV)=O PPIX ^•). This radical can delocalize to the protein to form a globin radical (Mb ^•), which can in turn catalyze lipid peroxidation by abstracting an electron from a lipid (LH). The lipid radical (L ^•) can then react to molecular oxygen to form the peroxyl radical (LOO ^•), which can propagate lipid peroxidation. Reducing co-substrates such as ApAP (RH) reduce the ferryl Mb back to its ferric state, thus inhibiting Mb-catalyzed lipid peroxidation.

Figure 2. Pathophysiologic mechanism leading to kidney injury following rhabdomyolysis

Release of Mb following rhabdomyolysis associated with hypovolemia induces renal vasoconstriction and Mb deposition in the kidney. Mb gets oxidized to its ferryl state inducing lipid peroxidation. Products of lipid peroxidation play a central role in the pathology via three different mechanisms: 1) the exacerbate lipid peroxidation by increasing the rate of formation of ferryl Mb; 2) they contribute to the oxidative injury of the kidney; and 3) they cause vasoconstriction preventing normal function of the kidney.