Nephrotoxic Effects Of Gentamicin Research Articles

Dihydromyricetin protects against gentamicin-induced nephrotoxicity via upregulation of renal SIRT3 and PAX2

AimGentamicin-induced nephrotoxicity limits its widespread use as an effective antibacterial agent. Oxidative stress, inflammatory cytokines and apoptotic cell death are major participants in gentamicin-induced nephrotoxicity. We therefore, investigated whether dihydromyricetin (DHM), the antioxidant and anti-inflammatory flavonoid, could protect against the nephrotoxic effects of gentamicin. MethodsMale Wistar rats administrated gentamicin (100 mg/kg/day, i.p.) for 8 days. DHM (400 mg/kg, p.o.) was concurrently given with gentamicin for 8 days. Control group received the vehicle of DHM and gentamicin. Histopathological examinations, biochemical measurements and immunohistochemical analyses were done at the end of the study. Key findingsTreatment with DHM improved the gentamicin induced deterioration of renal functions; serum levels of urea, creatinine and cystatin–C as well as urinary levels of Kim-1 and NGAL, the sensitive indicators for early renal damage, were declined. Additionally, DHM abrogated gentamicin-induced changes in kidney morphology. These nephroprotective effects were possibly mediated via decreasing renal gentamicin buildup, activating the antioxidant enzymes GSH, SOD and CAT and decreasing lipid peroxidation and nitric oxide levels. Further, DHM suppressed renal inflammation and apoptotic cell death by decreasing the expression of nuclear factor-kappa B (NF-κB), TNF-alpha and caspase-3. These effects were correlated to the upregulation of renal SIRT3 expression. Also, DHM activated the regeneration and replacement of injured tubular cells with new ones via enhancing PAX2 expression. SignificanceDHM is a promising therapeutic target that could prevent acute renal injury induced by gentamicin and help renal tubular cells to recover through its antioxidant, anti-inflammatory and antiapoptotic properties.

Punica granatum improves renal function in gentamicin-induced nephropathy in rats via attenuation of oxidative stress

BackgroundGentamicin is widely used as an antibiotic for the treatment of gram negative infections. Evidences indicates that oxidative stress is involved in gentamicin-induced nephrotoxicity. In Ayurvedic medicine, Punica granatum Linn. is considered as 'a pharmacy unto itself”. It has been claimed in traditional literature, to treat various kidney ailments due to its antioxidant potential. ObjectiveTo explore the possible mechanism of action of methanolic extract of P.granatum leaves (MPGL) in exerting a protective effect on gentamicin-induced nephropathy. Material and methodsAnimals were administered with gentamicin (80 mg/kg/day i.m.) and simultaneously with MPGL (100, 200 and 400 mg/kg p.o.) or metformin (100 mg/kg p.o.) for 8 days. A satellite group was employed in order to check for reversibility of nephrotoxic effects post discontinuation of gentamicin administration. At the end of the study, all the rats were sacrificed and serum–urine parameters were investigated. Antioxidant enzymes and tumor necrosis factor alpha (TNF-α) levels were determined in the kidney tissues along with histopathological examination of kidneys. ResultsIncrease in serum creatinine, urea, TNF-α, lipid peroxidation along with fall in the antioxidant enzymes activity and degeneration of tubules, arterioles as revealed by histopathological examination confirmed the manifestation of nephrotoxicity caused due to gentamicin. Simultaneous administration of MPGL and gentamicin protected kidneys against nephrotoxic effects of gentamicin as evidenced from normalization of renal function parameters and amelioration of histopathological changes. ConclusionData suggests that MPGL attenuated oxidative stress associated renal injury by preserving antioxidant enzymes, reducing lipid peroxidation and inhibiting inflammatory mediators such as TNF-α.

Nephrotoxic Effect of Gentamicin and Amikacin in Neonates with Infection

Background: Infection and its treatment as a common problem in children may induce different complications. Ampicillin and aminoglycosides, as choice drugs for this condition, may have many important side effects, such as nephrotoxic side effects. Therefore, the aim of this study was to evaluate the nephrotoxic effect of gentamicin and amikacin in neonates with infection. Methods: This clinical trial and double blind study was conducted on 80 children with aminoglycosides addministration. Initially, during hospital admission, serum and urine samples were collected for diagnosis of infection. Children based on their treatment were divided to 2 groups, 40 children were treated by ampicillin and amikacin and 40 children were treated by ampicillin and gentamicin, during a 7-day period. At the end of the treatment period, serum and urine samples were taken for measurment of laboratory variables, and GFR, for evaluation of kidney function. Results: Blood Urea Nitrogen (BUN), creatinine and GFR before and after treatment in the two groups did not have statistically significant differences (P > 0.05). In addition age, gender, birth age, infection type, occupation, and education of parents and milk type were equal in the 2 groups. Conclusions: Based on the present study, there were no significant differences between nephrotoxic effect of gentamicin and amikacin in the two groups.

Experimental gentamicin-induced nephrotoxicity in the sheep

Abstract The aim of the study was to investigate the nephrotoxic effects of gentamicin in adult male sheep, and to identify the earliest signs of toxicity and the extent of clinical and biochemical changes. Twenty clinically healthy yearling male Iranian fattailed sheep were injected with gentamicin sulfate at a daily dose of 80 mg/kg for 9-10 d when nephrotoxicosis was induced. Blood samples were collected weekly before and after induction of nephrotoxicosis. Gentamicin-induced nephrotoxicity was characterised by increased creatinine and urea levels in serum, electrolyte imbalances, occurrence of albuminuria, and renal dysfunction. Significant elevation in respiratory and heart rates were observed one week after treatment (P < 0.05). There was a noticeable increase in water consumption, lethargy, and loss of appetite in treated sheep. There were significant correlations between serum creatinine and potassium (P = 0.004, r = 0.759), sodium (P = 0.017, r = 0.501), and urea (P = 0.021, r = 0.617) levels. Additionally, significant negative correlations between serum total protein and albumin and creatinine (P = 0.023, r = -0.484) and urea (P = 0.036, r = -0.381) were found. At necropsy, the kidneys were pale, swollen, and wet on the cut surface, especially perirenal tissues and ureters were oedematous. These findings confirmed the previous reports in other species.

Reno-protective Role of Flunarizine (Mitochondrial Permeability Transition Pore Inactivator) against Gentamicin Induced Nephrotoxicity in Rats

This study was aimed to evaluate the role of flunarizine on gentamicin (GEM) induced nephrotoxicity in rat. Administration of GEM (40 mg/kg, s.c. for 10 consecutive days) significantly increased blood urea nitrogen (BUN), N-acetyl β-d-glucosaminidase (NAG), thiobarbituric acid reactive substances (TBARS) and total calcium whereas, decreased body weight, fractional excretion of sodium (FrNa), creatinine clearance (CrCl), reduced glutathione (GSH), mitochondrial cytochrome c oxidase (Cyt-C oxidase) and ATP levels resulting in nephrotoxicity. Further, flunarizine (100, 200 and 300 µmol/kg, p.o.) was administered to evaluate its renoprotective effect against GEM induced nephrotoxicity and the results were compared with cylcosporin A (CsA, 50 µmol/kg, p.o.). Flunarizine resulted in the attenuation of renal dysfunction and oxidative marker changes in rats subjected to GEM induced nephrotoxicity in a dose dependent manner. Medium and higher doses of flunarizine produced significant renal protective effect which was comparable to cyclosporin A. The results of this study clearly revealed that flunarizine protected the kidney against the nephrotoxic effect of GEM via mitochondrial permeability transition pore (MPTP) inactivation potential.

Rationality of Administered Gentamicin Dose in Cerebral Coma Patients Treated in an Intensive Care Unit

Gentamicin is still widely used in the treatment of patients in an intensive care unit (ICU). The efficacy of aminoglycosides correlates with the peak serum concentration (Cmax), and the toxicity with the minimum serum concentration (Cmin). The aim of this study was to determine Cmax and Cmin in serum of cerebral coma ICU patients when a dosage of gentamicin of 5 mg/kg body weight was administered once daily; to evaluate the rationality of mentioned dose; and to identify factors associated with these concentrations. Material and METHODS. A total of 24 ICU patients suffering from cerebral coma were included into this analysis. A dosage of gentamicin of 5 mg/kg body weight was administered once a day. Gentamicin concentrations were tested twice after the first dose infusion (immediately and 5 hours after 1-hour infusion). Cmax, Cmin, volume of distribution (Vd), and elimination half-life (T1/2) were obtained. RESULTS. The mean Cmax was 17.96 (SD, 4.31) µg/mL (range, 10.30-27.87 µg/mL). The desirable Cmax (≥ 20 µg/mL) was reached only in 6 patients (25%). Cmin was calculated using a special pharmacokinetic program "Kinetica." Cmin of 0.5 µg/mL was not exceeded in any patient. A correlative analysis indicated a significant inverse direct correlation between Cmax and Vd and between Cmax and treatment duration in the ICU. An inverse correlation was observed between Cmin and T1/2, evaluation of coma according to the Glasgow coma scale, and creatinine clearance. CONCLUSIONS. A dosage of 5 mg/kg body weight once a day was not sufficient in cerebral coma ICU patients. This dose was not associated with the nephrotoxic effect of gentamicin (additional risk factors were absent). It is recommended to obtain gentamicin concentration at two time points following administration of the first dose (e.g., immediately after 1-hour infusion and 5 hours later), and using a special pharmacokinetic software, to calculate a necessary dose and interval of administration.

Amelioration of gentamicin nephrotoxicity by green tea extract in uninephrectomized rats as a model of progressive renal failure

Rationale: Gentamicin (GM) is an effective antibiotic against severe infection but has limitations related to nephrotoxicity. This study investigates whether green tea extract (GTE), an antioxidant, could ameliorate the nephrotoxic effect of GM in uninephrectomized rats. Objectives: The right kidneys of 40 rats were surgically removed and 1 week later the animals were divided into four groups (n = 10). Group 1 served as control, Group 2 as GTE group, Group 3 as GM group, and Group 4 as GM+GTE group. Kidney function, inflammatory cytokine TNF-α, oxidant and antioxidant parameters of renal tissue, as well as histopathological studies were assessed. Main findings: Injecting uninephrectomized rats with GM induced renal dysfunction as shown by significant elevations in serum creatinine and urea. Serum TNF-α and oxidative stress parameters (superoxide anion and lipid peroxides) were also significantly increased. On the contrary, antioxidative parameters [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH)] were significantly decreased. Histopathological examination of renal tissue illustrated features of degeneration, marked cellular infiltration, tubular dilatation, and varying degrees of necrosis. GTE given to GM rats reduced these nephrotoxicity parameters. Serum creatinine, urea, and TNF-α were almost normalized in the GM+GTE group. The oxidative stress parameters were significantly decreased and the antioxidative parameters were significantly increased. Conclusion: GTE ameliorates GM-induced nephrotoxicity and oxidative damage by improving antioxidant defense and tissue integrity. Further human studies are necessary to demonstrate the antioxidant effects of GTE on renal diseases. Nevertheless, green tea (GT) may offer an inexpensive, nontoxic, and effective intervention strategy in subjects with a risk for GM-induced nephrotoxicity.

Protective Effect of Quercetin against Gentamicin-Induced Nephrotoxicity in Rats

Gentamicin (GM) is an antibiotic widely used in treating severe gram-negative infections. However, its clinical use is limited by its nephrotoxicity. Several lines of evidence indicate that free radicals are important mediators of gentamicin nephrotoxicity. Therefore, the aim of this work was to investigate the possible protective effect of the flavonoid quercetin, an antioxidant, on gentamicin-induced nephrotoxicity. For this purpose, rats were divided into four groups. First group served as a control and injected with the normal saline, second group was injected with quercetin (50 mg/kg/d, per os) for 7 d, third group was injected with gentamicin (80 mg/kg/d, intraperitoneally) for 7 d and the fourth group of animals was injected with quercetin plus gentamicin simultaneously for 7 d. Total protein levels were estimated in 24-h urine samples to assess kidney dysfunction. The rats were sacrificed on the seventh day and kidneys were collected for histopathological studies. Blood urea nitrogen (BUN) and creatinine levels were measured in the blood. Moreover, glutathione (GSH), lipid peroxide (TBARS) levels, superoxide dismutase (SOD) and catalase (CAT) activities were determined in renal tissues. GM-treated rats showed early kidney dysfunction as urinary total protein, BUN and serum creatinine levels were significantly increased. The significant decrease in GSH levels, SOD, CAT activities and increase in TBARS levels, indicated that GM-induced nephrotoxicity was mediated through oxidative stress reactions. Histopathological examination of GM-treated rats revealed degenerative changes in glomeruli and tubules. On the other hand, simultaneous administration of quercetin plus gentamicin protected kidney tissues against nephrotoxic effects of gentamicin as evidenced from amelioration of histopathological changes and normalization of kidney biochemical parameters.

THE COMBINED EFFECT OF CYCLOSPORINE A AND GENTAMICIN ON ENZYMURIA IN THE SPRAGUE-DAWLEY RAT

Male Sprague-Dawley rats (8 per group) were administered a single oral dose of cyclosporine A (10, 30 and 50 mg/day) for 5 days or vehicle (corn oil, 1.5 mL/kg) and urinary enzymes excretion was monitored. Only minor changes in enzymuria were observed in the 10 and 30 mg/kg group. However, in the 50 mg/kg group, nephrotoxicity was evident by significant increase in the excretion of N-acetyl-β-D-glucosaminidase (NAG), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH on day 2 of treatment. As chemotherapeutic drug interaction with cyclosporine A (CyA) is thought to aggravate its nephrotoxicity, the effect of combined CyA (30 mg/kg) and the antibiotic gentamicin (50 mg/kg) for 5 days was investigated. Gentamicin alone caused a significant enzymuria, whilst co-treatment of rats with CyA gave rise to increased changes in enzymuria on days 1 and 2, between the groups receiving gentamicin + vehicle and those receiving CyA + gentamicin. This was particularly marked by significant changes in LDH excretion. In contrast these observed differences were not paralleled by changes in serum creatinine and other functional parameters. Treatment with gentamicin, appears to enhance CyA nephrotoxicity, but only in the first 2 days, after this there was no significant differences between the two groups. Our data suggest that urinary enzyme measurements could serve as a valuable non-invasive means of monitoring renal performance in animals or humans who may be exposed to combination of drugs. CyA is found not to potentiate the nephrotoxic effect of gentamicin in the animal model used in this study. It therefore appears safe to use the combined therapy particularly in the treatment of transplant patients.

Insulin reverses the protection given by diabetes against gentamicin nephrotoxicity in the rat.

Rats with untreated diabetes mellitus are protected from gentamicin-induced nephrotoxicity. In order to evaluate the role of hyperglycemia, glycosuria, and polyuria in this phenomenon, miniosmotic pumps filled with insulin were implanted for 15 days in seven female Sprague-Dawley rats with streptozotocin-induced diabetes mellitus. Plasma glucose levels were successfully maintained under 126 mg/dl. To serve as the control group, eight age-matched diabetic (plasma glucose > 400 mg/dl) rats had miniosmotic pumps placed delivering only Ringer's solution. Six days after placement of the pumps, gentamicin (40 mg/Kg/day) was administered to all animals for 9 days. The insulin-treated diabetic rats exhibited clear signs of nephrotoxicity by Day 6 of gentamicin, whereas the diabetic control group remained free from any functional or morphological evidence of proximal tubular damage throughout the 9 days of the aminoglycoside administration. At the end of the experiment, the creatinine clearance in the insulin-treated diabetic group was 45% lower than in the untreated diabetic group (P < 0.005). In addition, there was a rise in plasma creatinine (P < 0.02), muramidase appeared in the urine, and mild patchy acute tubular necrosis of the renal cortex was observed by light microscopic examination. The insulin-treated group also accumulated more gentamicin in the renal cortex than the untreated animals (P < 0.005). It is concluded that protection against the nephrotoxic effects of gentamicin is a feature of untreated experimental diabetes mellitus in the rat and that correction of the hyperglycemic state with insulin reverses this resistance.

Comparison of serum and renal gentamicin concentrations with fractional urinary excretion tests as indicators of nephrotoxicity

Gentamicin was given to six sheep at a dosage rate of 80 mg/kg/day divided into three daily doses to cause nephrotoxicity. Peak serum gentamicin concentrations rose significantly throughout dosing (P less than 0.05), but trough serum gentamicin concentrations increased dramatically (P less than 0.01) from initial concentrations of 3.2-9.1 micrograms/ml to final trough concentrations of 31.5-195 micrograms/ml by 6-10 days on gentamicin. The serum gentamicin elimination half-life (t1/2) was doubled in each animal by approximately 6 days on therapy, with the sheep that were the most clinically affected by the nephrotoxic effects of gentamicin showing increases in t1/2 earlier than those sheep that remained less intoxicated. These changes occurred before many other clinical indicators of nephrotoxicity, with only urinary enzyme excretions preceding the changes in gentamicin elimination. Thus, alterations in the elimination of gentamicin may be one of the first clinical indicators of the occurrence of gentamicin-induced nephrotoxicity.

Enhanced urinary trypsin inhibitory activity in gentamicin-induced nephrotoxicity in rats

We delineated in rats, the relationship between trypsin inhibitory activity in the urine and the nephrotoxic effects of gentamicin, eg, proteinuria and deterioration of glomerular filtration rate (GFR), measured by creatinine clearance. Gentamicin, 70 mg/kg per day, was injected intraperitoneally for 6–10 successive days. Serum and urine gentamicin levels were determined by a microbiological test. Trypsin inhibitory activity was assayed by the casein digestion method. The results showed a steady increase in urinary trypsin inhibitory activity starting from the fourth injection day. The increased levels of urinary trypsin inhibitory activity were associated with increased levels of urinary gentamicin excretion ( r = 0.36, p < 0.02, n = 50 after the fourth injection day), and were significantly higher than in control groups ( p < 0.001). The urinary trypsin inhibitory activity was inversely correlated with the GFR ( r = −0.45, p < 0.01, after the second injection day). The serum trypsin inhibitory activity remained unchanged throughout the study period in all groups. These data suggest that increased urinary trypsin inhibitory activity may be involved in the pathogenesis of gentamicin-induced nephrotoxicity.