Protective Effects of Cilastatin against Vancomycin-Induced Nephrotoxicity

Abstract

Vancomycin is a very effective antibiotic for treatment of severe infections. However, its use in clinical practice is limited by nephrotoxicity. Cilastatin is a dehydropeptidase I inhibitor that acts on the brush border membrane of the proximal tubule to prevent accumulation of imipenem and toxicity. The aim of this study was to investigate the potential protective effect of cilastatin on vancomycin-induced apoptosis and toxicity in cultured renal proximal tubular epithelial cells (RPTECs). Porcine RPTECs were cultured in the presence of vancomycin with and without cilastatin. Vancomycin induced dose-dependent apoptosis in cultured RPTECs, with DNA fragmentation, cell detachment, and a significant decrease in mitochondrial activity. Cilastatin prevented apoptotic events and diminished the antiproliferative effect and severe morphological changes induced by vancomycin. Cilastatin also improved the long-term recovery and survival of RPTECs exposed to vancomycin and partially attenuated vancomycin uptake by RPTECs. On the other hand, cilastatin had no effects on vancomycin-induced necrosis or the bactericidal effect of the antibiotic. This study indicates that cilastatin protects against vancomycin-induced proximal tubule apoptosis and increases cell viability, without compromising the antimicrobial effect of vancomycin. The beneficial effect could be attributed, at least in part, to decreased accumulation of vancomycin in RPTECs.

Vancomycin‐Induced Kidney Injury: Animal Models of Toxicodynamics, Mechanisms of Injury, Human Translation, and Potential Strategies for Prevention

“…The visualization of large amounts of vancomycin at the brush border also points to either ongoing secretion or reabsorption of the drug at the apical side (i.e., from the urine) 57, 58 . In support, recent preclinical data have demonstrated vancomycin transport across the brush border membrane by apical endocytosis via dehydropeptidase 59 and megalin 60 and vancomycin‐mediated inhibition of the expression and function of P‐glycoprotein, an efflux transporter 61 . Although mechanistically plausible, the involvement of the multidrug and toxin extrusion (MATE1 and MATE2‐K) family of proteins in the secretion of vancomycin has yet to be demonstrated.…”

“…As such, an increase in malondialdehyde levels and a decrease in antioxidative enzyme activities – reduced glutathione peroxidase and superoxide dismutase – as indicators of oxidative stress have been reported in the kidney tissue of rats treated with vancomycin; antioxidants, including a superoxide dismutase conjugate, 78 reversed or prevented these effects and downstream histopathologic damage. In addition, the superoxides produced cause mitochondrial membrane depolarization and subsequent release of cytochrome C with activation of downstream caspases 59, 82 , ultimately leading to cell apoptosis.…”

Review of vancomycin-induced renal toxicity: an update

“…In experimental animals, coadministration (or pretreatment) of rats with antioxidative compounds that express superoxide dismutase attenuated proximal renal tubular injury with a favorable histological outcome [Oktem et al 2005;Nishino et al 2003]. Superoxide production by vancomycin causes depolarization of mitochondrial membrane potential with a release of cytochrome C, and a subsequent activation of both caspases 9 and 3 [Arimura et al 2012;Humanes et al 2015]. The latter is involved in apoptotic cell death.…”

“…These therapeutic agents enhance the survival of renal tubular cells by reducing DNA fragmentation, apoptosis and necrosis; and in certain instances by the modulation of autophagy [Huang et al 2016]. Nevertheless, in contrast to the effect of cilastatin previously discussed, it is unclear if antioxidative strategy would place a limitation on the bactericidal activity of vancomycin [Humanes et al 2015]. Clinical trials are therefore needed to validate the renal protective advantage of these agents in the human population.…”

Nephroprotective Effect of Nasturtium Officinale (Watercress) Ethanol Extract and Vitamin E on Vancomycin-Induced Nephrotoxicity in Rats

“…Several antioxidants including: vitamin E (8), 2, 3-dihydroxybenzoic acid (9), curcumin (10) and vitamin C (11) have been reported that reduces VIN. Based on these data, renal tubular ischemia due to the oxidative effects of VCM is the main known mechanism of VIN (5,12,13). ditional medicine, the leaves of the plant are widely used as diuretic, expectorant, blood purifier, hypoglycemic, and odontolgic (14)(15)(16)(17).…”