Molecular Mechanisms of Colistin-Induced Nephrotoxicity

Abstract

The emergence of multidrug resistant (MDR) infections and the shortage of new therapeutic options have made colistin, a polymyxin antibiotic, the main option for the treatment of MDR Gram-negative bacterial infections in the last decade. However, the rapid onset of renal damage often prevents the achievement of optimal therapeutic doses and/or forces the physicians to interrupt the therapy, increasing the risk of drug resistance. The proper management of colistin-induced nephrotoxicity remains challenging, mostly because the investigation of the cellular and molecular pharmacology of this drug, off the market for decades, has been largely neglected. For years, the renal damage induced by colistin was considered a mere consequence of the detergent activity of this drug on the cell membrane of proximal tubule cells. Lately, it has been proposed that the intracellular accumulation is a precondition for colistin-mediated renal damage, and that mitochondria might be a primary site of damage. Antioxidant approaches (e.g., ascorbic acid) have shown promising results in protecting the kidney of rodents exposed to colistin, yet none of these strategies have yet reached the bedside. Here we provide a critical overview of the possible mechanisms that may contribute to colistin-induced renal damage and the potential protective strategies under investigation.

Keywords: acute kidney injury; colistin; mitochondria; nephrotoxicity; polymyxins; proximal tubule.

Figure 1

Chemical structure of colistin A (polymyixin E1). A cyclic heptapeptide with a tripeptide side chain acylated at the N-terminus by a fatty acid tail.

Figure 2

Main sites of drug-induced kidney injury. Schematic representation of a nephron, the functional unit of the kidney. Each nephron is composed of a glomerulus and a tubule. The glomerulus filters the blood, producing an ultrafiltrate mainly composed by small molecules, from nutrients to ions. The ultrafiltrate enters the tubule in which at various segments (proximal tubule, Henle’s loop and distal tubule) it is modified to obtain the final urine in the collecting duct.

Figure 3

Lipid composition and distribution of prokaryotic and eukaryotic plasma membrane. Negatively charged phospholipids are enriched in the outer layer of prokaryotic membranes and in the inner layer of eukaryotic membranes. Cholesterol, a constituent of eukaryotic cells, stabilizes and protects the membrane from the colistin detergent activity.

Figure 4

Model of colistin re-absorption in proximal tubule cells. After glomerular filtration, colistin is taken up by proximal tubule cells by facilitative transport mediated by the human peptide transporter 2 (PEPT2) and the carnitine/organic cation transporter 2 (OCTN2) and by the megalin-mediated endocytosis.

Figure 5

Effect of colistin on isolated mitochondria. Freshly isolated mitochondria from mouse kidneys were exposed to a hydrophilic Ca²⁺-sensitive dye: calcium release from the mitochondria results in an increase in the fluorescent signal (top panel). Mitochondria were exposed to rhodamine 123, a membrane potential-sensitive) dye. The lower the membrane potential, the higher the rhodamine 123 fluorescence signal (λ_ex = 488 nm, λ_em = 527 nm) (bottom panel).