Adriamycin-induced Nephrotoxicity Research Articles

Standardized aqueous stem bark extract of Gmelina arborea roxb. possesses nephroprotection against adriamycin-induced nephrotoxicity in Wistar rats

Nephrotoxicity is a major limitation of adriamycin (ADR) chemotherapy. We hypothesized that administration of standardized aqueous bark extract of Gmelina arborea Roxb. (GA) (Family; Verbenaceae), a traditional therapeutic agent, may reduce the nephrotoxicity caused by ADR in Wistar rats. The dose-dependent nephroprotective activity of the standardized GA extract was investigated in ADR-induced (20 mg/kg, ip) nephrotoxicity in male Wistar rats (n = 6/group). The lyophilized powder of the aqueous refluxed (4 h) GA extract was administered at 100, 300 and 500 mg/kg doses orally for three consecutive days. Fosinopril sodium (0.09 mg/kg) was used as the positive control. Assessment of biochemical parameters on serum, urine and histopathology on H and E stained kidney sections were done at the end of the intervention. The treatment with GA and fosinopril decreased the elevation of serum creatinine, blood urea nitrogen, cystatin C, β2-microglobulin and loss of total protein in urine in nephrotoxic rats in a dose-dependent manner (p < 0.05). In contrast, serum concentrations of albumin and total protein were increased significantly (p < 0.05). H and E stained kidney sections showed an attenuation of renal parenchymal injury following the treatment. The aqueous extract of GA demonstrated antioxidant potential in vitro. Present findings conclude that the standardized aqueous extract of GA stem bark exerted a dose-dependent protection against ADR-induced nephrotoxicity in vivo and may be a promising adjunct in ADR chemotherapy.

Protective effect of melatonin and agomelatine on adriamycin-induced nephrotoxicity in rat model: a renal scintigraphy and biochemical study.

We aimed to determine the possible protective effects of melatonin and agomelatine on an animal model of adriamycin nephrotoxicity by 99mTc DMSA renal scintigraphy and biochemical methods. Ten weeks old 49 male Wistar rats were randomly separated into seven groups; namely control (CON), adriamycin (ADR), melatonin (MEL), agomelatine (AGO), melatonin + adriamycin (MEL+ADR), agomelatine + adriamycin (AGO+ADR) and melatonin + agomelatine + adriamycin (MEL+AGO+ADR) groups. Nephrotoxicity was induced by a three-dose of 18 mg/kg adriamycin, i.p. at a 24 h interval on the 5th, 6th and 7th days. A dose of melatonin and agomelatine (40 mg/kg/i.p, the same doses) were injected for 7 days before and after the injected of ADR (18 mg/kg, i.p.), respectively. On the 8th day of the experiment, all animals were evaluated and scintigraphic and biochemical parameters were assessed, respectively. ADR significantly increased blood urea nitrogen (1040 %) and plasma creatinine (1020 %), and decreased 99mTc DMSA uptake levels (59 %) compared to the control (p < 0.001). Pretreatment with MEL, AGO, MEL+AGO mitigated these abnormalities produced by ADR in the kidney (p < 0.001). 99mTc DMSA for the early determination of ADR-induced nephrotoxicity had an important role. Also, a significant correlation was found between biochemical and scintigraphy parameters. Adriamycin caused significant damages to kidneys that were reduced with MEL and AGO (Tab. 2, Fig. 3, Ref. 39).

The restoration of kidney mitochondria function by inhibition of angiotensin-II production in rats with acute adriamycin-induced nephrotoxicity

Adriamycin (ADR) is commonly used for many solid tumor treatments. Its clinical utility is, however, largely limited by the adverse reactions, are known to be nephrotoxic. The mechanism by which it induces kidney damage is still not completely understood, but its nephrotoxicity might relate to increase reactive oxidant status (ROS), mitochondrial dysfunction. Until now, neurohormonal activation of it is unclear. ADR might activate the renin angiotensin system. Angiotensin-II also induced ROS and mitochondrial dysfunction. The aim of this study was to investigate whether angiotensin-II production inhibition has the protective effect on attenuation of mitochondrial function in rats with acute ADR-nephrotoxicity or not. Rats were divided into five groups as a control, ADR, co-treated ADR with captopril (CAP), co-treated ADR with Aliskren, co-treated ADR with both CAP and Aliskren groups. Creatinine kinase (CK) levels were measured at the end of treatment period. The kidneys were homogenized and biochemical measurements were made in mitochondria, cytosol. Mitochondria membrane potential (MMP) and ATP levels were determined. ADR increased CK levels and oxidative stress in mitochondria too (p < 0.05). ADR significantly decreased MMP and ATP level in kidney mitochondria (p < 0.05). Co-administration with ADR and Aliskren and CAP improved the dissipation of MMP (p < 0.05). The decrease in ATP level was restored by treatment with inhibitors of ACE and renin. We concluded that inhibitors of angiotensin-II are effective against acute ADR induced nephrotoxicity via the restoration of MMP and ATP production and prevention of mitochondrial damage in vivo.

Effect of fenugreek (Trigonella foenum graecum) seeds on adriamycin-induced nephrotoxicity in albino rats

AbstractAdriamycin (ADR) is an anticancer drug used in treatment of a variety of neoplastic lesions. Its use is limited due to diverse toxicities including cardiotoxicity, hepatotoxicity and nephrotoxicity. The present work was conducted to study the effect of fenugreek seed extract on nephrotoxicity induced by ADR in albino rats. Administrating animals with a single dose of ADR (10 mg/kg body weight) induced histopathological, immunohistochemical and biochemical alterations. Kidneys of ADR-treated rats showed many histopathological alterations. The renal tubules were degenerated and the glomeruli were atrophied. The intertubular spaces were infiltrated by inflammatory leucocytic cells. An increase in expression of alfa-SMA was recorded. ADR caused marked elevation in serum creatinine and blood urea nitrogen. Moreover, ADR administration to animals significantly increased the concentration of malondialdehyde and decreased the activity of superoxide dismutase (SOD) in kidney tissues. These changes were time-dependent. Treating animals with ADR and aqueous seed extract of fenugreek (0.4 g/kg) led to an improvement in the histological structure of the kidney together with a decrease in expression of α-SMA. Urea and creatinine were significantly decreased. Moreover, fenugreek treatment reduced the concentration of malondialdehyde (lipid peroxidation marker) and increased the activity of antioxidant enzyme, SOD. In conclusion, the results of the present work indicated that fenugreek seeds had ameliorative effect on kidney damage induced by ADR and this may be mediated by its potent antioxidant effects

Effects of Vitamin D3 (Cholecalciferol) on Adriamycin-Induced Nephrotoxicity

Although immune-mediated pathogenesis in adriamycin (ADR)-induced nephropathy has been proposed recently, studies are lacking about the effects of immunmodulators, such as vitamin D, on ADR-induced nephrotoxicity. We hypothesized that vitamin D3 (cholecalciferol) would be beneficial on ADR‐induced nephropathy because of its immunmodulatory properties. Eighteen male Wistar rats were divided into three groups (n = 6): group 1 (control), group 2 (single ADR injection intravenously), and group 3 (similar single ADR injection intravenously + daily oral cholecalciferol for 21 days) were used in the study. A single high dose of ADR resulted in increased urinary protein: creatinine ratio for all three weeks of the experiment in both groups 2 and 3 compared with the controls. Histological examination of the kidney tissue revealed distinct tubular lesions as tubular necrosis, hyaline casts in tubular lumen, tubular degeneration, tubular dilatation, and tubular vacuolization in group 2 compared with group 1. These tubular lesions were significantly reduced in group 3 compared to group 2. The results of this study indicate that cholecalciferol causes satisfactory tubulointerstitial recovery in ADR-induced nephrotoxicity in rats.

Protective Effect of Simvastatin Against Adriamycin-Induced Nepherotoxicity in Rats; Biochemical and Histological Study

Introduction: The usefulness of adriamycin (ADR), a potent anti-tumor antibiotic, is limited by the development of life-threatening cardiomyopathy and nephropathy. The cellular changes leading to these toxicities are suggested to be mediated by increased free radicals and lipid peroxidation Aim of the study: The current study was aimed to investigate the protective role of simvastatin (SIM) on adriamycin-induced nephrotoxicity in rat using biochemical, and histological approaches. Material and methods: Twenty eight healthy male Swiss albino rats were used and divided into four groups : CONT (control), ADR (adriamycin treated), SIM (simvastatin treated), and SIM+ADR (simvastatin plus adriamycin treated). Blood samples were collected and used to determine the serum urea, creatinine, albumin, and total protein levels. Both kidneys were removed ,one of them was prepared for histological examinations and the other was stored at −70 °C for subsequent measurement of malondialdehyde (MDA), glutathione (GSH) contents and phase II antioxidants enzymes activities. Results: Glutathione (GSH) level, glutathione-s-transferase (GST) and DT-diphorase activities were decreased, while the lipid peroxidation was increased in kidney tissue. Administration of SIM (cumulative dose, 60 mg/kg body wt) in 12 equal injections (PO), before and concurrent with ADR, more or less prevented these nephropathic changes, normalized kidney function, and eliminated ascitis. Treatment with SIM was also accompanied by an increase in kidney GSH level as well as DT-diphorase activities with a concomitant decrease in lipid peroxidation. Histological examination revealed extensive and marked tubular necrosis in the ADR-treated kidney. Administration of Simvastatin reversed kidney damage with a marked reduction in tubular damage induced by ADR Conclusion: These data show that SIM can provide coma protection against ADR nephropathy. This protective effect of SIM may be related to the antioxidant status on the kidney

Protective Effect of Simvastatin Against Adriamycin-Induced Nepherotoxicity in Rats; Biochemical and Histological Study

Introduction: The usefulness of adriamycin (ADR), a potent anti-tumor antibiotic, is limited by the development of life-threatening cardiomyopathy and nephropathy. The cellular changes leading to these toxicities are suggested to be mediated by increased free radicals and lipid peroxidation Aim of the study: The current study was aimed to investigate the protective role of simvastatin (SIM) on adriamycin-induced nephrotoxicity in rat using biochemical, and histological approaches. Material and methods: Twenty eight healthy male Swiss albino rats were used and divided into four groups : CONT (control), ADR (adriamycin treated), SIM (simvastatin treated), and SIM+ADR (simvastatin plus adriamycin treated). Blood samples were collected and used to determine the serum urea, creatinine, albumin, and total protein levels. Both kidneys were removed ,one of them was prepared for histological examinations and the other was stored at −70 °C for subsequent measurement of malondialdehyde (MDA), glutathione (GSH) contents and phase II antioxidants enzymes activities. Results: Glutathione (GSH) level, glutathione-s-transferase (GST) and DT-diphorase activities were decreased, while the lipid peroxidation was increased in kidney tissue. Administration of SIM (cumulative dose, 60 mg/kg body wt) in 12 equal injections (PO), before and concurrent with ADR, more or less prevented these nephropathic changes, normalized kidney function, and eliminated ascitis. Treatment with SIM was also accompanied by an increase in kidney GSH level as well as DT-diphorase activities with a concomitant decrease in lipid peroxidation. Histological examination revealed extensive and marked tubular necrosis in the ADR-treated kidney. Administration of Simvastatin reversed kidney damage with a marked reduction in tubular damage induced by ADR Conclusion: These data show that SIM can provide coma protection against ADR nephropathy. This protective effect of SIM may be related to the antioxidant status on the kidney

The influence of lipoic acid on adriamycin-induced hyperlipidemic nephrotoxicity in rats.

Adriamycin widely used in the treatment of neoplastic conditions is nephrotoxic. In the present study the protective effect of lipoic acid was investigated in adriamycin-induced nephrotoxicity in adult male albino Wistar rats. Adriamycin-induced nephrotoxicity was characterized by hyperlipidemia, proteinuria, and hypoproteinemia, by decreased activities of the enzymes N-acetyl-beta-D-glucosaminidase and cathepsin D, by increased lipid peroxidation and decreases in serum catalase and glutathione activities, and by increased urinary and serum urea, creatinine and urinary glycosaminoglycans. Pretreatment with lipoic acid restored the changes, indicating that lipoic acid is renoprotective in adriamycin nephrotoxicity.

Renal toxicity of antineoplastic agents

Most of the drugs currently used in the treatment of cancer are highly cytotoxic and possess relatively low therapeutic selectivity. Given the major role of the kidney in the excretion of these drugs or their metabolites, it is perhaps surprising that clinically significant nephrotoxicity occurs with a limited number of drugs. Adriamycin induces a nephrotic syndrome in rats characterized by severe acute glomerular injury and sustained proteinuria. Tubular lesions subsequently develop, and the formation of tubular casts with resulting interstitial changes is accompanied by the appearance of glomerulosclerosis. Although the mechanism of adriamycin-induced nephrotoxicity is not known, it has been suggested that redox cycling may contribute to this toxicity by enhancing membrane lipid peroxidation, resulting in damage to kidney endoplasmic reticulum and mitochondrial membranes [l]. Mitocycin C is another redox-cycling drug with a cytotoxic mechanism of action that is very different from adriamycin. A hemolytic uremic syndrome of unknown pathogenesis has been reported in some patients treated with mitomycin C; this syndrome has been reproduced in’a unilateral perfusion study in the rat [2]. Nephrotoxicity has been reported for the nitrosoureas in both clinical and laboratory studies. Methyl-CCNU administered as a single, high dose produces acute proximal tubular necrosis in the rat; impaired tubular transport was evident 1 h after drug treatment. Proteinuria and decreased urine-concentrating ability accompanied necrosis of the papillary collecting ducts l-6 days later. Low-dose treatment resulted in a delayed-onset chronic progressive nephropathy involving polyuria, enzymuria, and decreased urine-concentrating ability [3,4]. Several lines of evidence point to the

Captopril protects from adriamycin-induced nephrotoxicity

Captopril protects from adriamycin-induced nephrotoxicity