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Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it?
Pharmacological Research 62 (2010) 179–186
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Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Review
Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it? Pitchai Balakumar a,∗ , Ankur Rohilla b , Arunachalam Thangathirupathi a a b
Department of Pharmacology, SB College of Pharmacy, Sivakasi 626 130, India Department of Pharmaceutical Sciences, Shri Gopi Chand Group of Institutions, Baghpat 250 609, India
a r t i c l e
i n f o
Article history: Received 14 April 2010 Received in revised form 20 April 2010 Accepted 21 April 2010 Keywords: Gentamicin Nephrotoxicity Pharmacological interventions
a b s t r a c t Aminoglycoside antibiotics are employed clinically because of their potent bactericidal activities, less bacterial resistance, post-antibiotic effects and low cost. However, drugs belong to this class are wellknown to cause nephrotoxicity, which limits their frequent clinical exploitation. Gentamicin, a commonly used aminoglycoside, is associated with an induction of tubular necrosis, epithelial oedema of proximal tubules, cellular desquamation, tubular fibrosis, glomerular congestion, perivascular edema and inflammation, which ultimately show the way to renal dysfunction. It is a matter of debate whether we have promising agents to prevent the incidence of gentamicin-induced nephrotoxicity. The present review critically discussed the pathogenesis of gentamicin-induced nephrotoxicity. In addition, based on the experimental and clinical studies, the possible therapeutic approach to prevent gentamicin-induced nephrotoxicity has been discussed. © 2010 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology of gentamicin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathological mechanisms pertaining to gentamicin-associated nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs having potential to prevent gentamicin-nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Aminoglycosides are employed in the treatment of severe gramnegative bacterial infections. However, their clinical exploitation is often associated with an induction of nephrotoxicity. Gentamicin, an aminoglycoside class of bactericidal antibiotic, is effective against gram-negative bacterial infections [1]. In spite of inducing nephrotoxicity, gentamicin is used clinically due to its wide spectrum of activities against gram-negative bacterial infections caused by Pseudomonas, Proteus, and Serratia [2–4]. The gentamicin-induced nephrotoxicity occurs by selective accumulation of the drug in renal proximal convoluted
∗ Corresponding author. Tel.: +91 9815557265. E-mail address: [email protected] (P. Balakumar). 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2010.04.004
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tubules that leads to loss of its brush border integrity [5]. The gentamicin-nephrotoxicity involves renal free radical generation, reduction in antioxidant defense mechanisms, acute tubular necrosis and glomerular congestion [1,6–9], resulting in diminished glomerular filtration rate and renal dysfunction. The pathological mechanisms pertaining to gentamicin-induced nephrotoxicity involve upregulation of transforming growth factor-beta (TGF-), elevation of endothelin-1, marked increase in monocyte/macrophage infiltration into the renal cortex and medulla, induction of oxidative stress and apoptosis and necrosis [8,10–13]. In past 2–3 decades, numerous pharmacological interventions have been demonstrated to prevent gentamicininduced nephrotoxicity. This review discussed key pathological mechanisms involved in gentamicin-induced nephrotoxicity along with the pharmacological interventions having potentials to prevent it.
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Fig. 1. Chemical structure of gentamicin.
2. Pharmacology of gentamicin Gentamicin was first isolated from Micromonospora purpurea, gram-positive bacteria widely present in water and soil, and was identified to have potential in treating various gram-negative bacterial infections [14,15]. Gentamicin inhibits bacterial protein synthesis by binding to 30S ribosomal subunit and preventing the formation of initiation complex with mRNA and also inducing the event of misreading of the mRNA message, leading to the production of defective proteins that afford bactericidal action [16–18]. Gentamicin, an aminoglycoside, comprised of two amino sugars joined to a hexose nucleus i.e. 2-deoxystreptamine by a glycosidic linkage (Fig. 1). Gentamicin is polycationic at physiological pH that makes it freely water soluble. It undergoes little metabolism and is well distributed in body tissues [14,19]. Gentamicin undergoes partial re-absorption by proximal tubular cells by adsorptive endocytosis that results in the fusion of endocytic vacuoles with lysosomes where the drug accumulates [20,21]. This accumulation induces the process of lysosomal phospholipidosis, resulting in tubular necrosis, which is a key pathological mechanism contributing to renal toxicity [22–26]. Gentamicin is not intended to be used orally since it is not absorbed to any appreciable extent from the small intestine. It is administered intravenously, intramuscularly or topically to treat bacterial infections. It is completely eliminated as unchanged form by glomerular filtration via urine [4,27]. 3. Pathological mechanisms pertaining to gentamicin-associated nephrotoxicity Gentamicin is a strongly cationic drug that binds to the negatively charged acidic phosphoinositide components of the brush border membrane of the proximal tubule, and they act on the cationic drug receptor, megalin, located deeply at the base of the brush border villi. The receptor–drug complex thus formed is rapidly internalized by a process of pinocytosis and taken up by lysosomes, where lysosomal phospholipidosis occurs that disrupts a number of renal intracellular processes [28,29]. Gentamicin-induced nephrotoxicity is functionally characterized by an increase in serum creatinine and blood urea nitrogen, incidences of albuminuria and urinary losses of carnitine, decrease in glomerular filtration rate, and renal dysfunction [30–35]. Gentamicin-induced nephrotoxicity is structurally associated with the occurrences of cellular desquamation, glomerular atrophy, tubular necrosis, tubular fibrosis, epithelial oedema of proximal tubules, glomerular hypertrophy, perivascular edema and inflammation and glomerular congestion [13,36–42]. Growing body of
experimental evidence suggested that multifaceted mechanisms are involved in gentamicin-nephrotoxicity (Figs. 2 and 3). Gentamicin increased macrophage infiltration and elevated TGF- levels that led to the progression of tubulointerstitial nephritis [8,13]. In addition, lysosomal phospholipidosis and apoptosis have been suggested to play a key role in gentamicin-induced nephrotoxicity [10,12,13]. Renal injury as a consequence of gentamicin-induced tubular necrosis stimulates inflammatory events by recruiting intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP-1) at the site of injury that enhance the migration of monocytes and macrophages to the site of tissue damage, ultimately leading to renal pathogenesis [8,43,44]. Gentamicin has been demonstrated to increase the generation of reactive oxygen species (ROS) like superoxide anions, hydroxyl radicals and hydrogen peroxides, and reactive nitrogen species (RNS) in the renal cortex that eventually lead to renal structural and functional deterioration [45–48]. Further, gentamicin-induced renal damage is linked with marked increases in lipoperoxidation levels [49], nitrotyrosine formation [50] and protein oxidation [51] in the renal cortex. Poly (ADP-ribose) polymerase (PARP), also known as poly (ADP-ribose) synthetase (PARS), is a nuclear enzyme depletes cellular NAD and ATP levels and thus drives the cell to necrosis. PARP activation has been noted in the proximal tubules of gentamicin-administered rats [50]. Hence, PARP activation and subsequent ATP depletion may also play a role in gentamicininduced tubular necrosis. Moreover, gentamicin has been shown to cause changes in the composition of lipid membranes executed by free radicals-mediated lipid peroxidation [52]. Furthermore, gentamicin-administered rat kidneys are more susceptible to ROS damage because of the induction of deficiency in antioxidant defense enzymes like superoxide dismutase and catalase [53,54]. It has been recently revealed that gentamicin-nephrotoxicity is associated with renal over-expression of p38-mitogen activated protein kinase (p38MAPK) and nuclear factor kappa B (NFkB) pathways [40]. 4. Drugs having potential to prevent gentamicin-nephrotoxicity Basic studies demonstrated several pharmacological interventions halting the incidence of gentamicin-induced nephrotoxicity. Fosfomycin, a broad-spectrum antibiotic indicated for the treatment of urinary tract infections, is clinically recognized to reduce aminoglycosides-induced nephrotoxicity. Fosfomycin, by depressing the iron release from renal cortex mitochondria, inhibited gentamicin-induced lipid peroxidation in the rat renal tissue and thus prevented nephrotoxicity [55]. Fleroxacin, a synthetic broad-spectrum antibiotic, has been reported to prevent gentamicin-induced nephrotoxicity by decreasing blood urea nitrogen and serum creatinine levels [56]. Gentamicin-induced decrease in glomerular filtration rate is associated with marked decline in the glomerular capillary ultrafiltration coefficient that occurs as a result of contraction of mesangial cells due to the availability of high cytosolic Ca2+ levels. Gentamicin markedly raised intracellular Ca2+ levels by activating both calcium influx from external source and calcium release from internal stores, and this increased intracellular Ca2+ levels was suggested to be responsible for renal mesangial cellular contraction and proliferation [57]. Hence gentamicin-induced increase in cytosolic free Ca2+ levels may play a key role in renal structural and functional damages. Therefore calcium channel blockers were thought to have ameliorative effects on gentamicin-nephrotoxicity. This contention was supported by the fact that treatment with nifedipine and amlodipine, dihydropyridine calcium channel blockers, reversed gentamicin-induced alterations in urinary protein levels, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine
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Fig. 2. Pathological mechanisms pertaining to gentamicin-induced nephrotoxicity MAPK, mitogen activated protein kinase; TNF-␣, tumor necrosis factor-alpha; PARS, poly (ADP-ribose) synthetase or poly (ADP-ribose) polymerase; NFkB, nuclear factor kappa B; TGF-, transforming growth factor-beta.
Fig. 3. Pathological role of reactive oxygen species in the induction of gentamicin-nephrotoxicity. ICAM-1, intercellular cellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; O2− , superoxide radical; OH− , hydroxyl radical; H2 O2 , hydrogen peroxide.
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and blood urea nitrogen that indicate their potential role in preventing gentamicin-induced nephrotoxicity [58]. Additionally, nitrendipine, a diisopyridine derived calcium channel blocker, afforded marked renal structural and functional protection against gentamicin-nephrotoxicity in rats [59]. In contrast, the inability of nitrendipine to protect against gentamicin nephrotoxicity in the rat was demonstrated [60]. Moreover, Li et al. [58] observed that nitrendipine had little effect, or even aggravated gentamicinnephrotoxicity. Additionally, it is worthwhile to mention that gentamicin-nephrotoxicity in rats was not modified by verapamil [61], rather verapamil exacerbated gentamicin-induced necrosis [62]. These studies raised questions about the protective effects of calcium channel blockers against gentamicin-nephrotoxicity. These results certainly suggest that all calcium channel blockers are not unique and may have different mode of action in modulating gentamicin-nephrotoxicity, and further studies are warranted to explore their defensive action against gentamicin-nephrotoxicity. Oxidative stress and nitrosative stress play a considerable role in gentamicin-induced nephrotoxicity. Drugs having direct or indirect antioxidant properties have been identified to prevent gentamicinnephrotoxicity in experimental studies. Treatment with carvedilol, a non-selective beta blocker/alpha-1 blocker with antioxidant property, prevented the gentamicin-induced nephrotoxicity by decreasing renal levels of malondialdehyde in rats [63]. Treatment with probucol, a powerful antioxidant, inhibited elevations in blood urea and creatinine levels that account for its renal protective effect against gentamicin-neprotoxicity in rats [36]. The genatmicin-nephrotoxicity was noted to be ameliorated by aminoguanidine, an antioxidant, by virtue if its ability to scavenge the free radical generation in the rat kidney [39]. Administration of trapidil, an antiplatelet and vasodilator drug, has been shown to enhance the level of the stable nitric oxide metabolite, nitrite, and thereby reduce the renal damage induced by gentamicin in rats [64]. It has been documented that moderate doses of vitamin C and vitamin E showed beneficial effects on renal preservation against gentamicin-induced nephrotoxicity in rats as evidenced by improved glomerular filtration rate and reduced renal oxidative stress [26]. Administration of N-imino-ethyl lysine (l-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), prevented gentamicin-induced decrease in gomerular filtration rate and increase in serum creatinine levels in rats [65]. On the other hand, N-omega-l-arginine methyl ester (l-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, aggravated gentamicinnephrotoxicity [65]. Supplementation of l-arginine, an immediate precursor of nitric oxide (NO), showed beneficial effects against gentamicin-nephrotoxocity in rats as evidenced by decreased blood urea nitrogen and creatinine levels [66,67]. It has been recently demonstrated that supplementation of l-carnitine, a quaternary ammonium compound possessing antioxidant effects, resulted in reversal of the increased levels of serum creatinine and blood urea nitrogen and thus protected rats from gentamicin-nephrtoxicity, where as d-carnitine aggravated gentamicin-induced acute renal failure [31]. S-allylcysteine, a free radical scavenger, has been reported to ameliorate the gentamicin-induced acute renal failure in rats by decreasing oxidative stress and preserving antioxidant enzymes activity in the renal cortex [46]. Administration of diallyl sulfide, a garlic-derived organosulfur compound with antioxidant properties, prevented gentamicin-nephrotoxicity in rats by decreasing oxidative stress in the renal cortex [33]. Dimethyl sulfoxide, a organosulfur compound having free-radical-scavenging potential, has been shown to lower the elevated plasma urea and creatinine concentrations, and reduce renal cortical thiobarbituric acid reactive substances in rats [68]. Treatment with ebselen, a selenoorganic drug, has been noted to prevent gentamicininduced renal oxidative damage and nitrosative damage in rats
[69]. Treatment with N-acetylcysteine, an antioxidant, prevented the gentamicin-induced renal tubular necrosis by interfering with peroxynitrite-related pathways in rats [70]. It has been demonstrated that S-allylmercaptocysteine, a free radical scavenger, ameliorated gentamicin-induced nephrotoxicity by scavenging hydroxyl radicals and decreasing renal oxidative and nitrosative stress in rats [25]. Administration of arabic gum, a complex polysaccharide, protected the rat from gentamicin-induced nephrotoxicity by inhibiting the production of oxygen free radicals and the occurrence of renal lipid peroxidation [71]. Lycopene, a bright red carotene pigment found in tomatoes, red carrots, watermelons and papayas, prevented gentamicin-induced nephrotoxicity by ameliorating the rise in renal malondialdehyde levels and blood creatinine levels in rats [72]. Curcumin, a yellow pigment isolated from turmeric, decreased the blood concentrations of creatinine and urea and enhanced the superoxide dismutase activity in renal cortex to prevent gentamicin-nephrotoxicity in rats [73]. Caffeic acid phenethyl ester, a potent free radical scavenger, prevented gentamicin-induced nephrotoxicity by reducing the generation of free radicals in the rat kidney [52]. Supplementation of thymoquinone, a compound with strong antioxidant properties derived from Nigella sativa, prevented the development of gentamicin-induced acute renal failure in rats by decreasing oxidative stress and preserving the activity of antioxidant enzymes [74]. Administration of resveratrol, an antioxidant flavonol, prevented gentamicin-induced neprotoxicity by decreasing the blood levels of urea and creatinine and reducing tubular damage and renal lipid peroxidation in rats [34]. It has been recently demonstrated that administration of quercetin, a flavanoid antioxidant, protected the rat from gentamicin-induced nephrotoxicity by enhancing reduced gluatathione, superoxide dismutase and catalase levels, and decreasing thiobarbituric acid reactive substances [9]. Antioxidant enzyme like superoxide dismutase had a defensive role against experimental gentamicin-nephrotoxicity by preserving renal antioxidant defense activities and thus reducing renal oxidative stress [75,76]. Treatment with M40403, a low molecular weight synthetic manganese containing superoxide dismutase mimetic having an ability to selectively remove superoxides, significantly prevented gentamicin-induced nitrotyrosine formation, poly (ADP-ribose) synthetase activation and tubular necrosis in rats [50]. The protein-chow diet with 20% casein showed protective effects against gentamicin-nephrotoxicity in rats [77]. In addition, dietary fish oil supplementation ameliorated gentamicin-induced renal metabolic alterations and oxidative damage in rats due to its antioxidant properties [78]. Other agents that have been documented to prevent gentamicin-induced nephrotoxicity include hormones such as melatonin and thyroxine [51,79]. A number of crude herbal extracts have been reported to ameliorate gentamicin-induced nephrotoxicity. The plant extract of Rhazya stricta has been noted to dose-dependently increase the superoxide dismutase activity and the reduced-form of glutathione and subsequently decrease lipid peroxides in the renal cortex of gentamicin-administered rats [49]. Garlic extract, by preserving antioxidant defense enzymes, decreased gentamicininduced oxidative stress in the rat renal cortex [54]. The ethanol extract of the roots of Cassia auriculata showed marked renal freeradical-scavenging effects against gentamicin-induced renal injury in rats [80]. The phenolic extract of soybean increased the activities of superoxide dismutase, catalase and reduced glutathione, which were found to be decreased in gentamicin-administered rats [81]. The leaf and seed aqueous extract of Phyllanthus amarus showed nephroprotection in gentamicin-administered rats by its antioxidant and free-radical-scavenging activities [82]. The aqueous-ethanolic extract of mushroom mycelium Morchella esculenta has been shown to prevent gentamicin-
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Table 1 Drugs having potential to prevent gentamicin-induced nephrotoxicity. S. no.
Pharmacological class
Pharmacological interventions
1 2 3 4 5 6 7 8 9 10 11 12 13
Antibiotics Calcium channel blockers Beta blocker Cytoprotective antianginal iNOS inhibitor NO precursor Hormones Antiplatelet Statin PPAR-␥ agonist TNF-␣ synthesis inhibitor Biguanides Antioxidants
14 15 16 17
Free radical scavengers Antioxidant enzyme Superoxide dismutase mimetic Herbal extracts
Fosfomycin, fleroxacin Nifedipine, amlodipine Carvedilol Trimetazine l-NIL l-arginine Melatonin, thyroxine Trapidil Atorvastatin Rosiglitazone Pentoxifylline Metformin Probucol, aminoguanidine, l-carnitine, ebselen, N-acetylcysteine, lycopene, curcumin, thymoquinone, fish oil, vitamin E, vitamin C, sesame oil, halofuginone, resveratrol, quercetin S-allylcysteine, diallyl sulfide, caffeic acid phenethyl ester, S-allylmercaptocysteine Superoxide dismutase M40403 Rhazya stricta, garlic, Cassia auriculata, soyabean, Phylanthus amarus, Morchella esculenta, green tea, Nigella sativa, Ligusticum wallichi, Viscum articulatum
induced nephrotoxicity in mice by enhancing renal antioxidant defense system [83]. Administration of Nigella sativa extract prevented gentamicin-induced nephrotoxicity in rats by reducing renal oxidative stress and enhancing antioxidant defense mechanism [84]. Taken together, pharmacological interventions like antioxidants, ROS scavengers and antioxidant enzymes are able to prevent gentamicin-induced nephrotoxicity. The pharmacological interventions having potential to prevent gentamicin-induced nephrotoxicity have been summarized in Table 1. 5. Current perspectives On the basis of aforementioned studies, it is apparent that gentamicin-induced nephrotoxicity principally involves renal inflammatory cascades, high renal oxidative stress and associated pathological signaling mechanisms. Thus agents having strong antioxidant and cellular anti-inflammatory properties may have ability to halt gentamicin-nephrotoxicity. In fact, recent studies identified few promising agents of having these properties to prevent gentamicin-nephrotoxicity. It has been demonstrated that treatment with halofuginone decreased the blood urea nitrogen and renal malondialdehyde levels that account for its renoprotective effects against gentamicin-nephrotoxicity [85]. Green tea extract has been noted to ameliorate gentamicininduced nephrotoxicity in rats by improving antioxidant defense mechanism, renal tissue integrity and energy metabolism, and decreasing renal oxidative damage [86]. Atorvastatin, a potent HMG-CoA reductase inhibitor, has been recently noted to ameliorate gentamicin-induced nephrotoxicity in rats by scavenging free radicals and inhibiting the renal expression of inflammatory mediators such as p38MAPK and NFkB [40]. Recent studies suggested that peroxisome proliferators-activated receptor (PPAR) ligands are having renoprotective potentials [87,88]. Rosiglitazone, a PPAR-gamma agonist belongs to thiazolidinedione class of anti-diabetics, has been shown to protect rat kidneys against gentamicin-nephrotoxicity by reducing free radical-mediated oxidative renal damage and inflammation [89]. Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine identified to be involved in gentamicin-nephrotoxicity by inducing loss of tubular cells. Treatment with pentoxifilline, a TNF-alpha synthesis inhibitor, ameliorated gentamicin-induced nephrotoxicity in rats by decreasing serum levels of creatinine and improving glomerular filtration rate and renal morphology [90]. Administration of tetramethylpyrazine, a compound purified from the rhizome of Ligusticum wallichi, has been demonstrated to prevent gentamicin-
induced loss of murine renal tubular cells by its anti-apoptotic and anti-inflammatory properties [91]. Metformin, a biguanide class of oral anti-diabetic agent, had an ability to diminish renal apoptosis executed by gentamicin-induced renal oxidative stress. In addition, metformin reduced gentamicin-nephrotoxicity by improving renal mitochondrial homeostasis in rats [92]. It has been recently reported that oleanolic acid, isolated from Viscum articulatum, protected the rat from gentamicin-nephrotoxicity by decreasing serum creatinine and albuminuria, and improving glomerular filtration rate and renal architecture [93]. Sesame oil supplementation attenuated gentamicin-induced renal oxidative stress and associated renal injury in rats by reducing renal oxygen free radicals generation and lipid peroxidation [94]. These studies certainly suggest that agents having strong antioxidant and cellular anti-inflammatory properties have ability to prevent gentamicin-induced experimental nephrotoxicity. However, their clinical defensive potentials are not known. Thus clinical studies are mandatory for exploring potential pharmacological interventions to prevent gentamicinnephrotoxicity. The gentamicin-nephrotoxicity may be aggravated in the presence of various factors such as older age, volume depletion and pre-existing renal dysfunction. The enhanced risk of nephrotoxicity was observed in patients received both gentamicin and furosemide [95], and thus diuretics should not be employed during aminoglycoside therapy. A once-daily dosing regimen of gentamicin (4 mg/kg every day) in patients was noted to be as effective as and was less nephrotoxic than more frequent dosing (1.33 mg/kg three times daily) [96]. A pharmacoeconomic study also revealed that once-daily dosing regimen resulted in a 58% reduction in gentamicin-associated hospital cost and a nephrotoxicity management savings of 70%/patient [97]. Thus administration of daily once gentamicin clinical dose may be less toxic than administration of the same dose divided into three doses per day. The reason behind this strategy may be explained from an animal study in which the high rate of gentamicin uptake by the renal tubular cells was noted after a continuous but single infusion of the drug. In addition, a steady-state elevation of serum gentamicin was associated with nonlinear increases in cortical levels, suggesting saturable uptake [98]. Thus the re-absorption and further renal accumulation of gentamicin can be reduced if it is used daily once. The chronopharmacological involvement of gentamicin-nephrotoxicity was investigated in patients, who were subjected to different time of drug administration (midnight to 7:30 AM, 8 AM to 3:30 PM, and 4 to 11:30 PM). The incidence of gentamicin-nephrotoxicity was noted to be occurred significantly and more frequently when the
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drug was administered during the rest period i.e. midnight to 7:30 AM. This result implicated the role of circadian variations in the glomerular filtration rate and enhanced renal availability of gentamicin during midnight to 7:30 AM [99]. Thus administration of gentamicin during the midnight to 7.30 AM periods is more likely to cause nephrotoxicity, which should be taken into account on its clinical use, and during this time the clinical application of gentamicin must be restricted. Preventing the re-absorption and renal drug accumulation would represent one of the best approaches to reduce gentamicinnephrotoxicity. It is interesting to note from a recent study that administration of trimetazine, a cytoprotective anti-ischemic agent used as an antianginal drug, may have attenuated gentamicinnephrotoxicity by inhibiting the re-absorption and consequently the accumulation of gentamicin in the rat proximal tubular cells [100]. 6. Concluding remarks Gentamicin induces nephrotoxicity by inhibiting protein synthesis in renal cells that specifically causes necrosis of cells in the renal proximal tubule, resulting in acute tubular necrosis, followed by acute renal failure. Gentamicin has been shown to increase the generations of ROS and RNS in the renal cortex that ultimately lead to renal damage. Despite causing nephrotoxicity, gentamicin is used in clinical practice because of its potent bactericidal activities and less bacterial resistance. Gentamicin should be carefully employed clinically to prevent nephrotoxicity especially in highrisk patients, and the renal function should be frequently assessed during its applications. Numerous pharmacological interventions halt the development of gentamicin-nephrotoxicity by primarily reducing renal oxidative stress, tubular cell death and renal inflammation. The pharmacological agent like trimetazine should be further investigated clinically since it has a potential to attenuate gentamicin-nephrotoxicity at an initial level by virtue of its ability to inhibit the re-absorption and accumulation of gentamicin in the rat proximal tubular cells. In fact, most of the pharmacological interventions preventing gentamicin-nephrotoxicity as mentioned in previous sections are extrapolated from animal studies. Unfortunately apparent evidences from human studies are scarce. Therefore clinical studies are mandatory to explore their bench-to-bedside effects in ameliorating gentamicinnephrotoxicity. Conflict of interest The authors declared no conflict of interest. Acknowledgments The authors express their gratitude to Shri. S. Sriram Ashok Ji, BE, Correspondent, and Shri. P. Dharmar, Secretary of SB College of Pharmacy, Sivakasi, India for their constant support to accomplish this study. References [1] Martinez-Salgado C, Lopez-Hernandez FJ, Lopez-Novoa JM. Glomerular nephrotoxicity of aminoglycosides. Toxicol Appl Pharmacol 2007;223:86–98. [2] del Valle DAS, Imbrogno MA, Fernadez E. Gentamicin in pediatric infections caused by gram-negative organisms. J Infect Dis 1969;119:453–6. [3] Miglioli PA, Silini R, Carzeri O, Grabocka E, Allerberger F. Antibacterial activity of gentamicin and ciprofloxacin against gram-negative bacteria: interactions with pig and calf sera. Pharmacol Res 1999;39:321–3. [4] Hendriks JGE, van Horn JR, van der Mei HC, Busscher HJ. Backgrounds of antibiotic loaded bone cement and prosthesis-related infection. Biomaterials 2004;25:545–56.
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Review
Gentamicin-induced nephrotoxicity: Do we have a promising therapeutic approach to blunt it? Pitchai Balakumar a,∗ , Ankur Rohilla b , Arunachalam Thangathirupathi a a b
Department of Pharmacology, SB College of Pharmacy, Sivakasi 626 130, India Department of Pharmaceutical Sciences, Shri Gopi Chand Group of Institutions, Baghpat 250 609, India
a r t i c l e
i n f o
Article history: Received 14 April 2010 Received in revised form 20 April 2010 Accepted 21 April 2010 Keywords: Gentamicin Nephrotoxicity Pharmacological interventions
a b s t r a c t Aminoglycoside antibiotics are employed clinically because of their potent bactericidal activities, less bacterial resistance, post-antibiotic effects and low cost. However, drugs belong to this class are wellknown to cause nephrotoxicity, which limits their frequent clinical exploitation. Gentamicin, a commonly used aminoglycoside, is associated with an induction of tubular necrosis, epithelial oedema of proximal tubules, cellular desquamation, tubular fibrosis, glomerular congestion, perivascular edema and inflammation, which ultimately show the way to renal dysfunction. It is a matter of debate whether we have promising agents to prevent the incidence of gentamicin-induced nephrotoxicity. The present review critically discussed the pathogenesis of gentamicin-induced nephrotoxicity. In addition, based on the experimental and clinical studies, the possible therapeutic approach to prevent gentamicin-induced nephrotoxicity has been discussed. © 2010 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacology of gentamicin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathological mechanisms pertaining to gentamicin-associated nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drugs having potential to prevent gentamicin-nephrotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Current perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Aminoglycosides are employed in the treatment of severe gramnegative bacterial infections. However, their clinical exploitation is often associated with an induction of nephrotoxicity. Gentamicin, an aminoglycoside class of bactericidal antibiotic, is effective against gram-negative bacterial infections [1]. In spite of inducing nephrotoxicity, gentamicin is used clinically due to its wide spectrum of activities against gram-negative bacterial infections caused by Pseudomonas, Proteus, and Serratia [2–4]. The gentamicin-induced nephrotoxicity occurs by selective accumulation of the drug in renal proximal convoluted
∗ Corresponding author. Tel.: +91 9815557265. E-mail address: [email protected] (P. Balakumar). 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2010.04.004
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tubules that leads to loss of its brush border integrity [5]. The gentamicin-nephrotoxicity involves renal free radical generation, reduction in antioxidant defense mechanisms, acute tubular necrosis and glomerular congestion [1,6–9], resulting in diminished glomerular filtration rate and renal dysfunction. The pathological mechanisms pertaining to gentamicin-induced nephrotoxicity involve upregulation of transforming growth factor-beta (TGF-), elevation of endothelin-1, marked increase in monocyte/macrophage infiltration into the renal cortex and medulla, induction of oxidative stress and apoptosis and necrosis [8,10–13]. In past 2–3 decades, numerous pharmacological interventions have been demonstrated to prevent gentamicininduced nephrotoxicity. This review discussed key pathological mechanisms involved in gentamicin-induced nephrotoxicity along with the pharmacological interventions having potentials to prevent it.
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Fig. 1. Chemical structure of gentamicin.
2. Pharmacology of gentamicin Gentamicin was first isolated from Micromonospora purpurea, gram-positive bacteria widely present in water and soil, and was identified to have potential in treating various gram-negative bacterial infections [14,15]. Gentamicin inhibits bacterial protein synthesis by binding to 30S ribosomal subunit and preventing the formation of initiation complex with mRNA and also inducing the event of misreading of the mRNA message, leading to the production of defective proteins that afford bactericidal action [16–18]. Gentamicin, an aminoglycoside, comprised of two amino sugars joined to a hexose nucleus i.e. 2-deoxystreptamine by a glycosidic linkage (Fig. 1). Gentamicin is polycationic at physiological pH that makes it freely water soluble. It undergoes little metabolism and is well distributed in body tissues [14,19]. Gentamicin undergoes partial re-absorption by proximal tubular cells by adsorptive endocytosis that results in the fusion of endocytic vacuoles with lysosomes where the drug accumulates [20,21]. This accumulation induces the process of lysosomal phospholipidosis, resulting in tubular necrosis, which is a key pathological mechanism contributing to renal toxicity [22–26]. Gentamicin is not intended to be used orally since it is not absorbed to any appreciable extent from the small intestine. It is administered intravenously, intramuscularly or topically to treat bacterial infections. It is completely eliminated as unchanged form by glomerular filtration via urine [4,27]. 3. Pathological mechanisms pertaining to gentamicin-associated nephrotoxicity Gentamicin is a strongly cationic drug that binds to the negatively charged acidic phosphoinositide components of the brush border membrane of the proximal tubule, and they act on the cationic drug receptor, megalin, located deeply at the base of the brush border villi. The receptor–drug complex thus formed is rapidly internalized by a process of pinocytosis and taken up by lysosomes, where lysosomal phospholipidosis occurs that disrupts a number of renal intracellular processes [28,29]. Gentamicin-induced nephrotoxicity is functionally characterized by an increase in serum creatinine and blood urea nitrogen, incidences of albuminuria and urinary losses of carnitine, decrease in glomerular filtration rate, and renal dysfunction [30–35]. Gentamicin-induced nephrotoxicity is structurally associated with the occurrences of cellular desquamation, glomerular atrophy, tubular necrosis, tubular fibrosis, epithelial oedema of proximal tubules, glomerular hypertrophy, perivascular edema and inflammation and glomerular congestion [13,36–42]. Growing body of
experimental evidence suggested that multifaceted mechanisms are involved in gentamicin-nephrotoxicity (Figs. 2 and 3). Gentamicin increased macrophage infiltration and elevated TGF- levels that led to the progression of tubulointerstitial nephritis [8,13]. In addition, lysosomal phospholipidosis and apoptosis have been suggested to play a key role in gentamicin-induced nephrotoxicity [10,12,13]. Renal injury as a consequence of gentamicin-induced tubular necrosis stimulates inflammatory events by recruiting intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP-1) at the site of injury that enhance the migration of monocytes and macrophages to the site of tissue damage, ultimately leading to renal pathogenesis [8,43,44]. Gentamicin has been demonstrated to increase the generation of reactive oxygen species (ROS) like superoxide anions, hydroxyl radicals and hydrogen peroxides, and reactive nitrogen species (RNS) in the renal cortex that eventually lead to renal structural and functional deterioration [45–48]. Further, gentamicin-induced renal damage is linked with marked increases in lipoperoxidation levels [49], nitrotyrosine formation [50] and protein oxidation [51] in the renal cortex. Poly (ADP-ribose) polymerase (PARP), also known as poly (ADP-ribose) synthetase (PARS), is a nuclear enzyme depletes cellular NAD and ATP levels and thus drives the cell to necrosis. PARP activation has been noted in the proximal tubules of gentamicin-administered rats [50]. Hence, PARP activation and subsequent ATP depletion may also play a role in gentamicininduced tubular necrosis. Moreover, gentamicin has been shown to cause changes in the composition of lipid membranes executed by free radicals-mediated lipid peroxidation [52]. Furthermore, gentamicin-administered rat kidneys are more susceptible to ROS damage because of the induction of deficiency in antioxidant defense enzymes like superoxide dismutase and catalase [53,54]. It has been recently revealed that gentamicin-nephrotoxicity is associated with renal over-expression of p38-mitogen activated protein kinase (p38MAPK) and nuclear factor kappa B (NFkB) pathways [40]. 4. Drugs having potential to prevent gentamicin-nephrotoxicity Basic studies demonstrated several pharmacological interventions halting the incidence of gentamicin-induced nephrotoxicity. Fosfomycin, a broad-spectrum antibiotic indicated for the treatment of urinary tract infections, is clinically recognized to reduce aminoglycosides-induced nephrotoxicity. Fosfomycin, by depressing the iron release from renal cortex mitochondria, inhibited gentamicin-induced lipid peroxidation in the rat renal tissue and thus prevented nephrotoxicity [55]. Fleroxacin, a synthetic broad-spectrum antibiotic, has been reported to prevent gentamicin-induced nephrotoxicity by decreasing blood urea nitrogen and serum creatinine levels [56]. Gentamicin-induced decrease in glomerular filtration rate is associated with marked decline in the glomerular capillary ultrafiltration coefficient that occurs as a result of contraction of mesangial cells due to the availability of high cytosolic Ca2+ levels. Gentamicin markedly raised intracellular Ca2+ levels by activating both calcium influx from external source and calcium release from internal stores, and this increased intracellular Ca2+ levels was suggested to be responsible for renal mesangial cellular contraction and proliferation [57]. Hence gentamicin-induced increase in cytosolic free Ca2+ levels may play a key role in renal structural and functional damages. Therefore calcium channel blockers were thought to have ameliorative effects on gentamicin-nephrotoxicity. This contention was supported by the fact that treatment with nifedipine and amlodipine, dihydropyridine calcium channel blockers, reversed gentamicin-induced alterations in urinary protein levels, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine
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Fig. 2. Pathological mechanisms pertaining to gentamicin-induced nephrotoxicity MAPK, mitogen activated protein kinase; TNF-␣, tumor necrosis factor-alpha; PARS, poly (ADP-ribose) synthetase or poly (ADP-ribose) polymerase; NFkB, nuclear factor kappa B; TGF-, transforming growth factor-beta.
Fig. 3. Pathological role of reactive oxygen species in the induction of gentamicin-nephrotoxicity. ICAM-1, intercellular cellular adhesion molecule-1; MCP-1, monocyte chemoattractant protein-1; O2− , superoxide radical; OH− , hydroxyl radical; H2 O2 , hydrogen peroxide.
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and blood urea nitrogen that indicate their potential role in preventing gentamicin-induced nephrotoxicity [58]. Additionally, nitrendipine, a diisopyridine derived calcium channel blocker, afforded marked renal structural and functional protection against gentamicin-nephrotoxicity in rats [59]. In contrast, the inability of nitrendipine to protect against gentamicin nephrotoxicity in the rat was demonstrated [60]. Moreover, Li et al. [58] observed that nitrendipine had little effect, or even aggravated gentamicinnephrotoxicity. Additionally, it is worthwhile to mention that gentamicin-nephrotoxicity in rats was not modified by verapamil [61], rather verapamil exacerbated gentamicin-induced necrosis [62]. These studies raised questions about the protective effects of calcium channel blockers against gentamicin-nephrotoxicity. These results certainly suggest that all calcium channel blockers are not unique and may have different mode of action in modulating gentamicin-nephrotoxicity, and further studies are warranted to explore their defensive action against gentamicin-nephrotoxicity. Oxidative stress and nitrosative stress play a considerable role in gentamicin-induced nephrotoxicity. Drugs having direct or indirect antioxidant properties have been identified to prevent gentamicinnephrotoxicity in experimental studies. Treatment with carvedilol, a non-selective beta blocker/alpha-1 blocker with antioxidant property, prevented the gentamicin-induced nephrotoxicity by decreasing renal levels of malondialdehyde in rats [63]. Treatment with probucol, a powerful antioxidant, inhibited elevations in blood urea and creatinine levels that account for its renal protective effect against gentamicin-neprotoxicity in rats [36]. The genatmicin-nephrotoxicity was noted to be ameliorated by aminoguanidine, an antioxidant, by virtue if its ability to scavenge the free radical generation in the rat kidney [39]. Administration of trapidil, an antiplatelet and vasodilator drug, has been shown to enhance the level of the stable nitric oxide metabolite, nitrite, and thereby reduce the renal damage induced by gentamicin in rats [64]. It has been documented that moderate doses of vitamin C and vitamin E showed beneficial effects on renal preservation against gentamicin-induced nephrotoxicity in rats as evidenced by improved glomerular filtration rate and reduced renal oxidative stress [26]. Administration of N-imino-ethyl lysine (l-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), prevented gentamicin-induced decrease in gomerular filtration rate and increase in serum creatinine levels in rats [65]. On the other hand, N-omega-l-arginine methyl ester (l-NAME), a non-selective nitric oxide synthase (NOS) inhibitor, aggravated gentamicinnephrotoxicity [65]. Supplementation of l-arginine, an immediate precursor of nitric oxide (NO), showed beneficial effects against gentamicin-nephrotoxocity in rats as evidenced by decreased blood urea nitrogen and creatinine levels [66,67]. It has been recently demonstrated that supplementation of l-carnitine, a quaternary ammonium compound possessing antioxidant effects, resulted in reversal of the increased levels of serum creatinine and blood urea nitrogen and thus protected rats from gentamicin-nephrtoxicity, where as d-carnitine aggravated gentamicin-induced acute renal failure [31]. S-allylcysteine, a free radical scavenger, has been reported to ameliorate the gentamicin-induced acute renal failure in rats by decreasing oxidative stress and preserving antioxidant enzymes activity in the renal cortex [46]. Administration of diallyl sulfide, a garlic-derived organosulfur compound with antioxidant properties, prevented gentamicin-nephrotoxicity in rats by decreasing oxidative stress in the renal cortex [33]. Dimethyl sulfoxide, a organosulfur compound having free-radical-scavenging potential, has been shown to lower the elevated plasma urea and creatinine concentrations, and reduce renal cortical thiobarbituric acid reactive substances in rats [68]. Treatment with ebselen, a selenoorganic drug, has been noted to prevent gentamicininduced renal oxidative damage and nitrosative damage in rats
[69]. Treatment with N-acetylcysteine, an antioxidant, prevented the gentamicin-induced renal tubular necrosis by interfering with peroxynitrite-related pathways in rats [70]. It has been demonstrated that S-allylmercaptocysteine, a free radical scavenger, ameliorated gentamicin-induced nephrotoxicity by scavenging hydroxyl radicals and decreasing renal oxidative and nitrosative stress in rats [25]. Administration of arabic gum, a complex polysaccharide, protected the rat from gentamicin-induced nephrotoxicity by inhibiting the production of oxygen free radicals and the occurrence of renal lipid peroxidation [71]. Lycopene, a bright red carotene pigment found in tomatoes, red carrots, watermelons and papayas, prevented gentamicin-induced nephrotoxicity by ameliorating the rise in renal malondialdehyde levels and blood creatinine levels in rats [72]. Curcumin, a yellow pigment isolated from turmeric, decreased the blood concentrations of creatinine and urea and enhanced the superoxide dismutase activity in renal cortex to prevent gentamicin-nephrotoxicity in rats [73]. Caffeic acid phenethyl ester, a potent free radical scavenger, prevented gentamicin-induced nephrotoxicity by reducing the generation of free radicals in the rat kidney [52]. Supplementation of thymoquinone, a compound with strong antioxidant properties derived from Nigella sativa, prevented the development of gentamicin-induced acute renal failure in rats by decreasing oxidative stress and preserving the activity of antioxidant enzymes [74]. Administration of resveratrol, an antioxidant flavonol, prevented gentamicin-induced neprotoxicity by decreasing the blood levels of urea and creatinine and reducing tubular damage and renal lipid peroxidation in rats [34]. It has been recently demonstrated that administration of quercetin, a flavanoid antioxidant, protected the rat from gentamicin-induced nephrotoxicity by enhancing reduced gluatathione, superoxide dismutase and catalase levels, and decreasing thiobarbituric acid reactive substances [9]. Antioxidant enzyme like superoxide dismutase had a defensive role against experimental gentamicin-nephrotoxicity by preserving renal antioxidant defense activities and thus reducing renal oxidative stress [75,76]. Treatment with M40403, a low molecular weight synthetic manganese containing superoxide dismutase mimetic having an ability to selectively remove superoxides, significantly prevented gentamicin-induced nitrotyrosine formation, poly (ADP-ribose) synthetase activation and tubular necrosis in rats [50]. The protein-chow diet with 20% casein showed protective effects against gentamicin-nephrotoxicity in rats [77]. In addition, dietary fish oil supplementation ameliorated gentamicin-induced renal metabolic alterations and oxidative damage in rats due to its antioxidant properties [78]. Other agents that have been documented to prevent gentamicin-induced nephrotoxicity include hormones such as melatonin and thyroxine [51,79]. A number of crude herbal extracts have been reported to ameliorate gentamicin-induced nephrotoxicity. The plant extract of Rhazya stricta has been noted to dose-dependently increase the superoxide dismutase activity and the reduced-form of glutathione and subsequently decrease lipid peroxides in the renal cortex of gentamicin-administered rats [49]. Garlic extract, by preserving antioxidant defense enzymes, decreased gentamicininduced oxidative stress in the rat renal cortex [54]. The ethanol extract of the roots of Cassia auriculata showed marked renal freeradical-scavenging effects against gentamicin-induced renal injury in rats [80]. The phenolic extract of soybean increased the activities of superoxide dismutase, catalase and reduced glutathione, which were found to be decreased in gentamicin-administered rats [81]. The leaf and seed aqueous extract of Phyllanthus amarus showed nephroprotection in gentamicin-administered rats by its antioxidant and free-radical-scavenging activities [82]. The aqueous-ethanolic extract of mushroom mycelium Morchella esculenta has been shown to prevent gentamicin-
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Table 1 Drugs having potential to prevent gentamicin-induced nephrotoxicity. S. no.
Pharmacological class
Pharmacological interventions
1 2 3 4 5 6 7 8 9 10 11 12 13
Antibiotics Calcium channel blockers Beta blocker Cytoprotective antianginal iNOS inhibitor NO precursor Hormones Antiplatelet Statin PPAR-␥ agonist TNF-␣ synthesis inhibitor Biguanides Antioxidants
14 15 16 17
Free radical scavengers Antioxidant enzyme Superoxide dismutase mimetic Herbal extracts
Fosfomycin, fleroxacin Nifedipine, amlodipine Carvedilol Trimetazine l-NIL l-arginine Melatonin, thyroxine Trapidil Atorvastatin Rosiglitazone Pentoxifylline Metformin Probucol, aminoguanidine, l-carnitine, ebselen, N-acetylcysteine, lycopene, curcumin, thymoquinone, fish oil, vitamin E, vitamin C, sesame oil, halofuginone, resveratrol, quercetin S-allylcysteine, diallyl sulfide, caffeic acid phenethyl ester, S-allylmercaptocysteine Superoxide dismutase M40403 Rhazya stricta, garlic, Cassia auriculata, soyabean, Phylanthus amarus, Morchella esculenta, green tea, Nigella sativa, Ligusticum wallichi, Viscum articulatum
induced nephrotoxicity in mice by enhancing renal antioxidant defense system [83]. Administration of Nigella sativa extract prevented gentamicin-induced nephrotoxicity in rats by reducing renal oxidative stress and enhancing antioxidant defense mechanism [84]. Taken together, pharmacological interventions like antioxidants, ROS scavengers and antioxidant enzymes are able to prevent gentamicin-induced nephrotoxicity. The pharmacological interventions having potential to prevent gentamicin-induced nephrotoxicity have been summarized in Table 1. 5. Current perspectives On the basis of aforementioned studies, it is apparent that gentamicin-induced nephrotoxicity principally involves renal inflammatory cascades, high renal oxidative stress and associated pathological signaling mechanisms. Thus agents having strong antioxidant and cellular anti-inflammatory properties may have ability to halt gentamicin-nephrotoxicity. In fact, recent studies identified few promising agents of having these properties to prevent gentamicin-nephrotoxicity. It has been demonstrated that treatment with halofuginone decreased the blood urea nitrogen and renal malondialdehyde levels that account for its renoprotective effects against gentamicin-nephrotoxicity [85]. Green tea extract has been noted to ameliorate gentamicininduced nephrotoxicity in rats by improving antioxidant defense mechanism, renal tissue integrity and energy metabolism, and decreasing renal oxidative damage [86]. Atorvastatin, a potent HMG-CoA reductase inhibitor, has been recently noted to ameliorate gentamicin-induced nephrotoxicity in rats by scavenging free radicals and inhibiting the renal expression of inflammatory mediators such as p38MAPK and NFkB [40]. Recent studies suggested that peroxisome proliferators-activated receptor (PPAR) ligands are having renoprotective potentials [87,88]. Rosiglitazone, a PPAR-gamma agonist belongs to thiazolidinedione class of anti-diabetics, has been shown to protect rat kidneys against gentamicin-nephrotoxicity by reducing free radical-mediated oxidative renal damage and inflammation [89]. Tumor necrosis factor (TNF)-alpha is a pro-inflammatory cytokine identified to be involved in gentamicin-nephrotoxicity by inducing loss of tubular cells. Treatment with pentoxifilline, a TNF-alpha synthesis inhibitor, ameliorated gentamicin-induced nephrotoxicity in rats by decreasing serum levels of creatinine and improving glomerular filtration rate and renal morphology [90]. Administration of tetramethylpyrazine, a compound purified from the rhizome of Ligusticum wallichi, has been demonstrated to prevent gentamicin-
induced loss of murine renal tubular cells by its anti-apoptotic and anti-inflammatory properties [91]. Metformin, a biguanide class of oral anti-diabetic agent, had an ability to diminish renal apoptosis executed by gentamicin-induced renal oxidative stress. In addition, metformin reduced gentamicin-nephrotoxicity by improving renal mitochondrial homeostasis in rats [92]. It has been recently reported that oleanolic acid, isolated from Viscum articulatum, protected the rat from gentamicin-nephrotoxicity by decreasing serum creatinine and albuminuria, and improving glomerular filtration rate and renal architecture [93]. Sesame oil supplementation attenuated gentamicin-induced renal oxidative stress and associated renal injury in rats by reducing renal oxygen free radicals generation and lipid peroxidation [94]. These studies certainly suggest that agents having strong antioxidant and cellular anti-inflammatory properties have ability to prevent gentamicin-induced experimental nephrotoxicity. However, their clinical defensive potentials are not known. Thus clinical studies are mandatory for exploring potential pharmacological interventions to prevent gentamicinnephrotoxicity. The gentamicin-nephrotoxicity may be aggravated in the presence of various factors such as older age, volume depletion and pre-existing renal dysfunction. The enhanced risk of nephrotoxicity was observed in patients received both gentamicin and furosemide [95], and thus diuretics should not be employed during aminoglycoside therapy. A once-daily dosing regimen of gentamicin (4 mg/kg every day) in patients was noted to be as effective as and was less nephrotoxic than more frequent dosing (1.33 mg/kg three times daily) [96]. A pharmacoeconomic study also revealed that once-daily dosing regimen resulted in a 58% reduction in gentamicin-associated hospital cost and a nephrotoxicity management savings of 70%/patient [97]. Thus administration of daily once gentamicin clinical dose may be less toxic than administration of the same dose divided into three doses per day. The reason behind this strategy may be explained from an animal study in which the high rate of gentamicin uptake by the renal tubular cells was noted after a continuous but single infusion of the drug. In addition, a steady-state elevation of serum gentamicin was associated with nonlinear increases in cortical levels, suggesting saturable uptake [98]. Thus the re-absorption and further renal accumulation of gentamicin can be reduced if it is used daily once. The chronopharmacological involvement of gentamicin-nephrotoxicity was investigated in patients, who were subjected to different time of drug administration (midnight to 7:30 AM, 8 AM to 3:30 PM, and 4 to 11:30 PM). The incidence of gentamicin-nephrotoxicity was noted to be occurred significantly and more frequently when the
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drug was administered during the rest period i.e. midnight to 7:30 AM. This result implicated the role of circadian variations in the glomerular filtration rate and enhanced renal availability of gentamicin during midnight to 7:30 AM [99]. Thus administration of gentamicin during the midnight to 7.30 AM periods is more likely to cause nephrotoxicity, which should be taken into account on its clinical use, and during this time the clinical application of gentamicin must be restricted. Preventing the re-absorption and renal drug accumulation would represent one of the best approaches to reduce gentamicinnephrotoxicity. It is interesting to note from a recent study that administration of trimetazine, a cytoprotective anti-ischemic agent used as an antianginal drug, may have attenuated gentamicinnephrotoxicity by inhibiting the re-absorption and consequently the accumulation of gentamicin in the rat proximal tubular cells [100]. 6. Concluding remarks Gentamicin induces nephrotoxicity by inhibiting protein synthesis in renal cells that specifically causes necrosis of cells in the renal proximal tubule, resulting in acute tubular necrosis, followed by acute renal failure. Gentamicin has been shown to increase the generations of ROS and RNS in the renal cortex that ultimately lead to renal damage. Despite causing nephrotoxicity, gentamicin is used in clinical practice because of its potent bactericidal activities and less bacterial resistance. Gentamicin should be carefully employed clinically to prevent nephrotoxicity especially in highrisk patients, and the renal function should be frequently assessed during its applications. Numerous pharmacological interventions halt the development of gentamicin-nephrotoxicity by primarily reducing renal oxidative stress, tubular cell death and renal inflammation. The pharmacological agent like trimetazine should be further investigated clinically since it has a potential to attenuate gentamicin-nephrotoxicity at an initial level by virtue of its ability to inhibit the re-absorption and accumulation of gentamicin in the rat proximal tubular cells. In fact, most of the pharmacological interventions preventing gentamicin-nephrotoxicity as mentioned in previous sections are extrapolated from animal studies. Unfortunately apparent evidences from human studies are scarce. Therefore clinical studies are mandatory to explore their bench-to-bedside effects in ameliorating gentamicinnephrotoxicity. Conflict of interest The authors declared no conflict of interest. Acknowledgments The authors express their gratitude to Shri. S. Sriram Ashok Ji, BE, Correspondent, and Shri. P. Dharmar, Secretary of SB College of Pharmacy, Sivakasi, India for their constant support to accomplish this study. References [1] Martinez-Salgado C, Lopez-Hernandez FJ, Lopez-Novoa JM. Glomerular nephrotoxicity of aminoglycosides. Toxicol Appl Pharmacol 2007;223:86–98. [2] del Valle DAS, Imbrogno MA, Fernadez E. Gentamicin in pediatric infections caused by gram-negative organisms. J Infect Dis 1969;119:453–6. [3] Miglioli PA, Silini R, Carzeri O, Grabocka E, Allerberger F. Antibacterial activity of gentamicin and ciprofloxacin against gram-negative bacteria: interactions with pig and calf sera. Pharmacol Res 1999;39:321–3. [4] Hendriks JGE, van Horn JR, van der Mei HC, Busscher HJ. Backgrounds of antibiotic loaded bone cement and prosthesis-related infection. Biomaterials 2004;25:545–56.
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