Molecular Mechanisms of Rhabdomyolysis-Induced Kidney Injury: From Bench to Bedside

Abstract

Rhabdomyolysis-induced acute kidney injury (RIAKI) occurs following damage to the muscular sarcolemma sheath, resulting in the leakage of myoglobin and other metabolites that cause kidney damage. Currently, the sole recommended clinical treatment for RIAKI is aggressive fluid resuscitation, but other potential therapies, including pretreatments for those at risk for developing RIAKI, are under investigation. This review outlines the mechanisms and clinical significance of RIAKI, investigational treatments and their specific targets, and the status of ongoing research trials.

Keywords: RIAKI; acute kidney injury; rhabdomyolysis; treatment.

Figure 1

Rhabdomyolysis-induced acute kidney injury is caused by myoglobin. (a) Muscle takes damage and releases myoglobin and other metabolites into circulation. (b) Myoglobin is circulated to the kidney for filtration, causing capillary damage and hypovolemia en route. (c) Myoglobin reaches the kidney and is filtered by the glomerulus. (d) Heme oxygenase-1 degrades heme transported into the proximal tubule by Heme carrier protein 1 to release free ferrous iron. (e) Iron bound to substrates, including myoglobin, is transported into the proximal kidney tubule by megalin and cubilin, further increasing the concentration of free ferrous iron. (f) Ferritin, which oxidizes Fe(2+) to Fe(3+) and stores it, fails to keep up with incoming free ferrous. Fe(2+) reacts with hydrogen peroxide in the Fenton reaction, producing hydroxyl radicals, lipid peroxidation, and overwhelming superoxide dismutase activity, resulting in the formation of damaging reactive oxygen species (ROS). (g) Myoglobin combines with Tamm-Horsfall protein (THP), found in the thick segment of the ascending limb, forming a precipitate. (h) THP-Myoglobin precipitate forms obstructive tubular casts in the distal convoluted tubule. (i) Urine output decreases, resulting in reduced potassium excretion and perturbation of water, pH, and sodium balances, putting further pressure on the vascular system. ROS, reactive oxygen species.

Figure 2

Kidney inflammation during RIAKI and associated molecular targets. Myoglobin from the tubular system infiltrates into the interstitial space, resulting in immune activation. Studies thus far demonstrate that primarily innate immune cells are involved in kidney inflammation during RIAKI. These cells include monocytes, macrophages, natural killer cells, and neutrophils. Resident macrophages express IL-1β receptor, activation of which promotes production of inflammatory cytokines and cytotoxic macrophage extracellular traps, similar to neutrophil extracellular traps. Depicted in this figure are several potential molecular targets that have not yet been investigated in RIAKI. IL-β, interleukin 1 beta; IL-R, interleukin receptor.

Figure 3

Neutrophils infiltrate the kidney in a mouse model of RIAKI. (a) Schematic of a RIAKI mouse model, generated by glycerol injection into the anterior thigh after 4 hours of water deprivation, resulting in rhabdomyolysis and acute kidney injury. The kidney immune landscape was then characterized by flow cytometry 24 hours after injection. (b) Representative flow cytometry plots depicting immune cells (live, single cell, CD45+), identifying kidney lymphocytes (CD11b-) and myeloid cells (CD11b+) from glycerol- or saline-treated mice. (c) Representative flow cytometry plots depicting different myeloid cell populations from glycerol-treated or saline-treated mice. By gating on CD11b+ myeloid cells, Ly6CloLy6G- myeloid cells (mainly resident macrophages), Ly6ChiLy6G- monocytes (inflammatory monocytes), and Ly6CmidLy6G+ neutrophils were identified. (d) Quantification of kidney immune cells 24 hrs after glycerol injection, demonstrating an increase in myeloid cells, particularly neutrophils, in glycerol-injected mice. n = 2/group. CD, cluster of differentiation; CD11b, integrin alpha M; CD45, Protein tyrosine phosphatase, receptor type, C.