How Does Colistin-Induced Nephropathy Develop and Can It Be Treated?

Abstract

Colistin is an old antibiotic used in the treatment of Gram-negative infections. It was once suspended because of its nephrotoxic effect but has since been reintroduced due to multidrug-resistant bacterial infections. The pathogenesis of colistin-associated nephropathy has not been clarified, and there is currently no effective therapeutic or prophylactic agent available. The aim of this study was to investigate the roles of caspase-associated apoptosis and caspase 1, calpain 1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) expression in the pathogenesis of colistin-associated nephrotoxicity and the effect of grape seed proanthocyanidin extract (GSPE) in preventing it. Twenty-four rats were divided into three groups: control, colistin, and colistin plus GSPE (colistin؉GSPE). Colistin-associated nephropathy was induced by the administration of 300,000 IU/kg of body weight/day colistin intraperitoneally for 7 days. The experiment was discontinued on the seventh day. Blood was collected for measurements of blood urea nitrogen (BUN) and creatinine levels. Histopathological examination of kidney tissue and caspase 1 and 3, iNOS, eNOS, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and calpain 1 staining was also performed. Significant increases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed for the colistin group compared to the control group. Significant decreases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed in the colistin؉GSPE group compared to the colistin group. Our study shows, for the first time in the literature, that caspase-mediated apoptosis, iNOS, caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy. GSPE had a renoprotective effect, as shown by the lowered levels of these mediators.

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

“…Lycopene has been shown to interact with ROS and thereby to prevent ROSinduced tissue and cellular damage (35). Consistent with previous studies, we revealed that colistin-induced nephrotoxicity is associated with significantly increased MDA levels and a concomitant decrease in the levels of antioxidant enzymes CAT, SOD, and GSH (Table 2) (16,18,60,61). In the present study, lycopene treatment restored the levels of all of these biomarkers to the normal range observed in the untreated control group (Table 2), confirming its nephroprotective effect.…”

“…*, P Ͻ 0.05; **, P Ͻ 0.01 (compared to the control group); #, P Ͻ 0.05; ##, P Ͻ 0.01 (compared to the colistin group). [16][17][18]55). Increased production of ROS is an important mechanism in colistin-induced nephrotoxicity and neurotoxicity (17,(56)(57)(58).…”

“…Caspase-3 is a key biomarker of apoptosis (18), which can be activated by both intrinsic and extrinsic apoptotic pathways and consequently lead to DNA breakdown (14,57,62). Several studies showed that activated caspase-3 played a key role in colistin-induced apoptosis in rat kidney tissue (12,17,18). The mitochondrion is a major producer of ROS and plays a central role in the process of oxidative stress (58,63).…”

“…Reactive oxygen species (ROS) molecules are mainly generated by mitochondria and are among the major mediators of oxidative stress; they initiate renal cell apoptosis, which finally leads to renal dysfunction (14,15). ROSmediated oxidative stress plays a key role in colistin-induced nephrotoxicity (12,(16)(17)(18).…”

Colistín en la era post-antibiótica

“…En la gran mayoría de los casos la falla renal aparece en los primeros siete días de tratamiento y la función renal se recupera tras la suspensión de éste, en al menos 90% de los casos 10 . El mecanismo específico de la nefropatía inducida por colistín no se conoce completamente, aunque modelos animales recientes sugieren que en su patogenia estarían involucrados el estrés oxidativo y la activación de algunas vías apoptóticas, como las caspasas 82 . La neurotoxicidad es otra de las preocupaciones de los clínicos al usar polimixina E, aunque su incidencia es mucho menor que el daño renal, es leve y además resuelve rápidamente tras la discontinuación del antimicrobiano 79 .…”