Renal changes associated with naproxen sodium administration in cynomolgus monkeys.

Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.     

Tobramycin-induced changes in renal histology of fetal and newborn Sprague-Dawley rats.

Effects on renal development were studied using tobramycin (TBM) as a model compound. Pregnant Sprague-Dawley rats were injected i.p. with TBM at 30 or 60 mg/kg body weight/day on gestational days (GD) 10-19. Kidneys from dams and conceptuses were examined on GD 20 and on postnatal day (PD) 9. The dosing regimen caused in dams moderate proximal tubular alterations and increased concentrations in serum creatinine. Fetal kidneys showed granularity and swelling of proximal tubule cells at the 30 mg/kg dose, poor glomerular differentiation at the 60 mg/kg dose, increased glomerular density at both doses, and no changes on macroscopic examination at either dose. In newborns were observed a moderate developmental delay and tubular lesions at the higher dose, and dose-related increases of glomerular density and relative medullary area at both doses. All findings were more pronounced in males. A maturational disruption of the tubular structures possibly leading to increased glomerular density was attributed to TBM exposure during renal organogenesis in the rat.     

Biomarkers of collecting duct injury in Han-Wistar and Sprague-Dawley rats treated with N-phenylanthranilic Acid

N-phenylanthranilic acid is a chloride channel blocker that causes renal papillary necrosis in rats. Studies were conducted in two strains of male rats to evaluate novel biomarkers of nephrotoxicity. Han-Wistar rats were given daily oral doses of 50, 350, or up to 700 mg/kg/day of NPAA, and Sprague-Dawley rats were given 50 or 400 mg/kg/day of NPAA. Rats were euthanized on days 8 and 15. The candidate kidney injury biomarkers renal papillary antigen-1 (RPA-1, for collecting duct injury), clusterin (for general kidney injury), α-glutathione-S-transferase (a proximal tubular marker), and μ-glutathione-S-transferase (a distal tubular marker) were measured in urine by enzyme immunoassay. Characteristic degeneration and necrosis of the collecting duct and renal papilla were observed in Han-Wistar rats at the high dose on day 8 and at the mid and high doses on day 15, and in Sprague-Dawley rats given the high dose on days 8 and 15. Increases in urinary RPA-1, and to a lesser extent urine clusterin, were generally associated with the presence of collecting duct injury and were more sensitive than BUN and serum creatinine. On the other hand, decreases in α-glutathione-S-transferase without proximal tubule lesions in both strains and decreases in μ-glutathione-S-transferase in Sprague-Dawley rats only were not associated with morphological proximal or distal tubule abnormalities, so both were of less utility. It was concluded that RPA-1 is a new biomarker with utility in the detection of collecting duct injury in papillary necrosis in male rats.     

Antioxidant protecting effects of vitamin B6 at reducing hemodynamic toxicity of gentamicin in rat model of nephrotoxicity

Routine therapeutic use of gentamicin in patients with preexisting renal failure may confront us with the toxic effects of aminoglycosides in the kidney known as nephrotoxicity. It is a common and often overlooked clinical entity that presents itself in the setting of oxidative stress-associated diseases in older individuals with renal failure. In this study, we investigated the antioxidant protecting effects of vitamin B₆ in the kidney, with a view on vasoregulatory role of renal pyridoxal 5′-phosphate at reducing the hemodynamic toxicity of gentamicin. Hence, 50 male Sprague–Dawley rats were randomly assigned in five groups to receive a corresponding dose of either normal saline, vitamin B₆ (100 mg/kg/bw; i.m.) or gentamicin alone (80 mg/kg/bw; i.m.), or in combination with vitamin B₆ at low (100 mg/kg/bw; i.m.) and high dose (200 mg/kg/bw; i.m.) for 10 days as animal model of nephrotoxicity. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in local and systemic oxidative stress and a decrease in glomerular functions as result of early hemodynamic toxicity. Histopathological examinations of renal tissues revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of the experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies in HVB group showed the protecting effects of supplemented vitamin B₆ at a high dose, including a slowdown in urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and ATPase activity up to 50 % when compared to low-dose rats and controls. In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin B₆ consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin B₆ prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.     

Influence of zinc supplementation on histopathological changes in the stomach,liver, kidney,brain, pancreas and spleen during subchronic exposure of Wistar rats to glyphosate

A subchronic toxicity study was carried out to determine the glyphosate-induced histopathological changes in the stomach, liver, kidney, brain, pancreas and spleen of rats and the attendant ameliorative effect when pretreated with zinc at the dose rate of 50 mg/kg body weight. The rats were exposed to two doses of the glyphosate (375 and 14.4 mg/kg body weight) for the period of 8 weeks which was the duration of the study, and some groups were exposed to the glyphosate after pretreatment with zinc. The histopathological changes recorded during the study were only in the rats exposed to the glyphosate at the dose rate of 375 mg/kg body weight except the vacuolation encountered in the brains and haemosiderosis in the spleens of rats exposed to zinc alone. Degenerated mucosal epithelial cells which involved the muscularis mucosa and the glands in the stomachs of rats were seen microscopically. Hepatic cells degeneration especially at the portal areas of the livers of rats was observed. The histopathological examination of the kidneys showed glomerular degeneration, mononuclear cells infiltration into the interstices of the tubules and tubular necrosis. The conspicuous changes seen in the brains were neuronal degeneration. Pancreatic acinar cells were degenerated while the spleen of the rats showed depopulated splenic cells in both the red and the white pulps. It was concluded that zinc supplementation in rats prior to glyphosate exposure ameliorated the histopathological changes observed in the stomach, liver, kidney, brain, pancreas and spleen with no observable alteration in the histoarchitecture in the organs of the zinc-supplemented rats.     

Toxicity of cis-diamminedichloroplatinum (II) (cisplatin) in the frog, Rana pipiens

The toxicity of the anti-cancer drug cis-diamminedichloroplatinum (II) (cisplatin), at 2 to 40 mg per kg, was studied in the frog, Rana pipiens. The LD50 for the drug was approximately 17 mg per kg. Major non-nervous system toxicity occurred in the kidney. Renal failure was manifested as anasarca and increasing blood urea nitrogen (BUN). Histopathological changes included acute tubular necrosis and tubular dilatation, which were more severe at higher doses. Interstitial fibrosis occurred after prolonged survival after a single dose. Ultrastructurally, there was increased electron-dense material in tubular cells, but no specific changes in mitochondria or nuclear structures were seen. Gastro-intestinal toxicity was less severe than in other species and was more prominent at higher doses. Pathological changes consisted of epithelial nuclear atypia and apoptosis. By electron microscopy, there was increased separation of cell borders, depletion of chylomicrons and mucin granules and increases in electron-dense material. Again no specific mitochondrial or nuclear changes were seen. Relatively slight changes were seen in the liver, consisting of altered distribution of rough endoplasmic reticulum and dispersion of nuclear chromatin. Minimal pathology was demonstrated in the haematopoietic system or in the gonads. Thus toxicity of cisplatin in the frog is similar to that seen in mammals, including rodents and man.     

Gentamicin and tobramycin nephrotoxicity. A morphologic and functional comparison in the rat.

Fischer 344 rats were treated with tobramycin or gentamicin, 40 mg/kg/day, for up to 10 days or with tobramycin, 120 mg/kg/day, for up to 14 days. Serum creatinine and BUN at the time of sacrifice were determined, and kidney tissues were examined by light and electron microscopy. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis which was nearly universal at the end of 10 days. Their BUN and creatinine levels rose progressively over the same period. Even at the higher dosage, tobramycin therapy resulted in only rare foci of proximal tubular necrosis and minimal elevation of BUN and creatinine. Although they occurred later and were substantially less severe, the ultrastructural changes induced by tobramycin were the same as those seen following gentamicin administration. These results indicate that the mechanism of tobramycin-induced renal injury is probably similar to that of gentamicin and that tobramycin is significantly less nephrotoxic in this experimental model.     

Tissue kim-1 and urinary clusterin as early indicators of Cisplatin-induced acute kidney injury in rats

The kidney is one of the main targets of drug toxicity, and early detection of renal damage is critical in preclinical drug development. A model of cisplatin-induced nephrotoxicity in male Sprague Dawley rats treated for 1, 3, 5, 7, or 14 days at 1 mg/kg/day was used to monitor the spatial and temporal expression of various indicators of kidney toxicity during the progression of acute kidney injury (AKI). As early as 1 day after cisplatin treatment, positive kidney injury molecule-1 (Kim-1) immunostaining, observed in the outer medulla of the kidney, and changes in urinary clusterin indicated the onset of proximal tubular injury in the absence of functional effects. After 3 days of treatment, Kim-1 protein levels in urine increased more than 20-fold concomitant with a positive clusterin immunostaining and an increase in urinary osteopontin. Tubular basophilia was also noted, while serum creatinine and blood urea nitrogen levels were elevated only after 5 days, together with tubular degeneration. In conclusion, tissue Kim-1 and urinary clusterin were the most sensitive biomarkers for detection of cisplatin-induced kidney damage. Thereafter, urinary Kim-1 and osteopontin, as well as clusterin immunostaining accurately correlated with the histopathological findings. When AKI is suspected in preclinical rat studies, Kim-1, clusterin, and osteopontin should be part of urinalysis and/or IHC can be performed.     

Vitamin B6 dose-dependently ameliorates renal hemodynamic toxicity of cisplatin in rat model of nephrotoxicity: the histopathologic and biochemical findings

Despite its significant anticancer activity, the clinical use of cisplatin is often limited by its undesirable side effects in the kidney known as nephrotoxicity. It is a common and often overlooked clinical entity that presents itself in the setting of oxidative stress-associated diseases in older individuals with renal failure. In this study, we investigated the antioxidant-protecting effects of vitamin B₆ in the kidney, with a view on the vasoregulatory role of renal pyridoxal 5′-phosphate at reducing the hemodynamic toxicity of cisplatin. Hence, 50 male Sprague–Dawley rats were randomly assigned in one of five groups of the study to receive a corresponding dose of either normal saline, vitamin B₆ (200 mg/kg/bw; i.m.) or cisplatin alone (7 mg/kg/bw; i.m.), or in combination with vitamin B₆ at low (100 mg/kg/bw; i.m.) and high dose (200 mg/kg/bw; i.m.) for 10 days as animal model of renal failure. Daily administration of cisplatin at a dose of 7 mg/kg/bw resulted in a significant increase in local and systemic oxidative stress of the kidney and a decrease in glomerular function as a result of early hemodynamic toxicity. Histopathological examinations of renal tissues revealed acute tubular necrosis with hyaline cast formation triggered by cisplatin over 9 days of the study, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies in HVB group showed the protecting effects of supplemented vitamin B₆ at a high dose, including a slowdown in urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and ATPase activity up to 50 % when compared to the low-dose rats and controls. In high-dose animals, the normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that the antioxidant property of vitamin B₆ consistently increases with the dose intensity. The present study also provided evidence that high dose of vitamin B₆ prevented both functional and histological renal changes induced by cisplatin in rats, more efficient than low dose of the vitamin.     

全反式维甲酸对生长发育期大鼠实质器官的损伤

目的 探讨体内过量全反式维甲酸（ATRA）对生长发育期SD大鼠的脑、心、肺、肝、肾和脾的影响。方法 以48只3周雄性SD大鼠为实验对象,随机分为对照组和3个实验组,ATRA剂量分别为40、60、80 mg/(kg·d),每组12只,进行连续10 d ATRA灌胃处理,记录SD大鼠每日体重,于灌胃第10天解剖称量各器官的重量以及计算脏器指数,然后对各器官进行HE染色。结果 ATRA灌胃后,与对照组比较,40 mg/(kg·d) ATRA组肾指数升高,体重变化差异无统计学意义;60 mg/(kg·d) ATRA组体重降低,心、肾指数升高,脾脏重量降低;80 mg/(kg·d)ATRA组体重明显降低,脑、心、肾指数升高,脑、脾重量降低;HE染色显示,与对照组比较,ATRA处理组的肺泡壁增厚,肾小管上皮细胞有空泡样改变,脾脏红髓出现较多巨噬细胞,而大脑、肝脏、心肌无明显组织学变化。结论 体内过量全反式维甲酸能够对生长发育期SD大鼠的肺、肾和脾有一定的损伤作用。     

Safety evaluation of recombinant staphylokinase in rhesus monkeys

Recombinant staphylokinase (rSTAR) is a profibrinolytic agent of bacterial origin. The objective of this study was to assess the toxicity of rSTAR administered with bolus intravenous infusion in rhesus monkeys (2/sex/group) at the dosages of 0, 4, 14, and 49 mg/kg/day for 2 weeks. The clinical signs were thickening of the skin in all animals and mild hematoma formation in three dosage groups at the injection sites. There were no effects on body weight, absolute or relative organ weights, ophthalmology, or electrocardiogram. Urinalysis indicated that 2 monkeys in 14 or 49 mg/kg/day group developed proteinuria and mild hematuria. Increases in serum BUN levels (14 and 49 mg/kg/day), ALT activity, and bilirubin levels (49 mg/kg/day), and decreases in red blood cell counts, hemoglobin concentrations and Hct values (49 mg/kg/day) were observed at week 2. Significant prolongtion of APTT, PT, and TT (14 and 49 mg/kg/day), and decreases in circulating plasminogen levels (3 treatment groups) were noted. Dose-dependent increases in the titers of anti-rSTAR antibodies and neutralizing rSTAR activity were observed in the three treated groups. Increased neutralizing rSTAR activity diminished the phamacologic effects of rSTAR (ie, prolonged APTT, PT, and TT approaching baseline levels at week 2). Histopathological findings included hemorrhage, and perivascular inflammatory cell infiltration at the injection sites, heptocellular degeneration characterized as cytoplasmic eosinophilia, vacuolation and condensed nuclei (49 mg/kg/day), effusion of RBCs and plasma within some Bowman's capsules and hyaline casts within the lumen of some renal tubules in the kidneys (14 and 49 mg/day/kg), and mild to moderate megakaryocyte hypoplasia with varying levels of pyknotic nuclei at all dose levels. Immune deposits in glomeruli in the kidneys from the three treated groups were detected. These changes were reversible following a 4-week recovery period. In the present preclinical evaluation of toxicity in monkeys, rSTAR is well toleratte at doses up to 49 mg/kg/day. The toxic target organs are the liver, kidney, and bone marrow.     

Tissue injury and repair in the rat kidney after exposure to cisplatin or carboplatin

Cisplatin (cis-diamminedichloroplatinum II) has emerged as an anticancer drug of considerable value for the chemotherapy of several human neoplasms. However, this agent often causes renal toxicity, which appears to be the dose-limiting untoward effect. The present animal study was undertaken to compare, with regard to kidney injury and renal tissue repair, cisplatin and carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II), a platinum derivative more recently introduced in clinics. Female Sprague-Dawley rats (four animals per group) were treated ip with cisplatin (4 or 8 mg/kg, delivered in four consecutive daily injections) or carboplatin (40 mg/kg given in one injection) and terminated 4, 7, and 21 days after drug administration. One hour prior to sacrifice, each animal received ip 200 microCi of [3H]thymidine for the measurement of DNA synthesis and cell proliferation (frequency of S-phase cells in renal tissue, determined by histoautoradiography). Cisplatin, particularly at 8 mg/kg, caused severe tubular injury (acute tubular necrosis) culminating in a long-lasting cystic tubular dilatation in the outer stripe of outer medulla. Tubular damage was followed by a sharp proliferative response, indicative of tubular regeneration. However, the proliferative activity was still above basal level at the end of the observation period, suggesting that the tissue repair process had not reached completeness 3 weeks after cisplatin administration. In contrast, carboplatin only induced focal tubular necrosis in proximal tubules. Distal and collecting tubules also showed ultrastructural evidence of hydropic degeneration after exposure to the latter drug. Renal tubular injury associated with carboplatin was followed by a mild proliferative response. From this study, we can infer that carboplatin is less nephrotoxic than cisplatin, but still causes histopathological alterations in renal tissue. Furthermore, the lesser nephrotoxicity of carboplatin has a primary origin and is not due to a more efficient tissue repair reaction.     

Dose-related protecting effects of vitamin C in gentamicin-induced rat nephrotoxicity: a histopathologic and biochemical study

Gentamicin remains the mainstay in treatment of gram-negative infections, despite its potential ototoxicity and nephrotoxicity. In this study, we investigated dose-related protecting effects of vitamin C against gentamicin-induced rat nephrotoxicity. Hence, 50 male albino Wistar rats were randomly divided into five equal groups to receive a corresponding dose of either normal saline as control, vitamin C (200 mg/kg/bw, i.m.) or gentamicin alone (80 mg/kg/bw, i.m.) or in combination with vitamin C at low dose (200 mg/kg/bw, i.m.; LVG) and high dose (600 mg/kg/bw, i.m.) for 9 days. Daily administration of gentamicin at a dose of 80 mg/kg resulted in a significant increase in oxidative stress in renal tissues and plasma and a concomitant decrease in the creatinine clearance and renal blood flow as result of early hemodynamic toxicity. Histopathological examinations revealed acute tubular necrosis with hyaline cast formation triggered by gentamicin over 9 days of experiment, in addition to interstitial nephritis and tubular epithelial loss. Further biochemical studies showed protecting effects of supplemented vitamin C at a high dose, including slowdown in the urinary enzyme activity, a significant decrease in plasma lipid peroxidation, and an increased tissue superoxide dismutase activity with recovery in the glomerular hemodynamicity and the ATPase activity up to 50% when compared to controls and low-dose rats (LVG). In high-dose animals, normal glomerular and tubular function on recovery from toxic renal failure led us to conclude that antioxidant properties of vitamin C consistently increase with dose intensity. The present study also provided evidence that high dose of vitamin C prevented both functional and histological renal changes induced by gentamicin in rats, more efficient than low dose of the vitamin.     

Clinicopathological and tissue indicators of para-aminophenol nephrotoxicity in sprague-dawley rats

A model of para-aminophenol (PAP) nephrotoxicity in Sprague-Dawley rats was utilized to characterize potential indicators of toxicity in the kidney and in biofluids, and to chronicle the progression of acute renal injury. Rats were administered PAP at a low or high dose and examined terminally at 6, 24 and 48 hours (4 animals/group with matching controls). Acute tubular necrosis was observed in the medullary rays (low and high doses) and the outer stripe of outer medulla (high dose only) as early as 6 hours postdosing. Starting at 24 hours, regeneration of the tubular epithelium was evident in both low and high dose studies. Associated with the tubular lesions, we observed elevation of urinary alpha -glutathione S-transferase levels, an indicator of proximal tubular injury. By immunohistochemistry of the kidney, decreased gamma -glutamylcysteine synthetase expression correlated with tubular injury, especially at high dose, whereas elevation of vimentin, osteopontin, and Ki-67 expression was concurrent with tubular regeneration. Clusterin and kidney injury molecule-1 displayed expression patterns characteristic of both renal injury and regeneration. Taken together, this study provided insight into the progression of nephrotoxicity, and allowed the evaluation of potential urinary and tissue protein biomarkers that could complement the early detection of acute tubular injury.     

Prediction of nephrotoxicant action and identification of candidate toxicity-related biomarkers

A vast majority of pharmacological compounds and their metabolites are excreted via the urine, and within the complex structure of the kidney,the proximal tubules are a main target site of nephrotoxic compounds. We used the model nephrotoxicants mercuric chloride, 2-bromoethylamine hydrobromide, hexachlorobutadiene, mitomycin, amphotericin, and puromycin to elucidate time- and dose-dependent global gene expression changes associated with proximal tubular toxicity. Male Sprague-Dawley rats were dosed via intraperitoneal injection once daily for mercuric chloride and amphotericin (up to 7 doses), while a single dose was given for all other compounds. Animals were exposed to 2 different doses of these compounds and kidney tissues were collected on day 1, 3, and 7 postdosing. Gene expression profiles were generated from kidney RNA using 17K rat cDNA dual dye microarray and analyzed in conjunction with histopathology. Analysis of gene expression profiles showed that the profiles clustered based on similarities in the severity and type of pathology of individual animals. Further, the expression changes were indicative of tubular toxicity showing hallmarks of tubular degeneration/regeneration and necrosis. Use of gene expression data in predicting the type of nephrotoxicity was then tested with a support vector machine (SVM)-based approach. A SVM prediction module was trained using 120 profiles of total profiles divided into four classes based on the severity of pathology and clustering. Although mitomycin C and amphotericin B treatments did not cause toxicity, their expression profiles were included in the SVM prediction module to increase the sample size. Using this classifier, the SVM predicted the type of pathology of 28 test profiles with 100% selectivity and 82% sensitivity. These data indicate that valid predictions could be made based on gene expression changes from a small set of expression profiles. A set of potential biomarkers showing a time- and dose-response with respect to the progression of proximal tubular toxicity were identified. These include several transporters (Slc21a2, Slc15, Slc34a2), Kim 1, IGFbp-1, osteopontin, alpha-fibrinogen, and Gstalpha.     

Immunolocalization of Kim-1, RPA-1, and RPA-2 in kidney of gentamicin-, mercury-, or chromium-treated rats: relationship to renal distributions of iNOS and nitrotyrosine

Immunohistochemical studies for kidney injury molecule-1 (Kim-1), renal papillary antigen-1 (RPA-1), and renal papillary antigen-2 (RPA-2) were conducted to explore their relationship to inducible nitric oxide synthase (iNOS) and nitrotyrosine expression. Male Sprague-Dawley rats were exposed to gentamicin (100 mg/kg/day Gen, sc, for 3 days), mercury (0.25 mg Hg/kg, iv, single dose), or chromium (5 mg Cr/kg, sc, single dose) and kidney tissue was examined 24 hours or 72 hours after the last dose of the nephrotoxicant. Another group of kidneys was evaluated 24 hours after rats were administered 3 daily doses (50, 100, 150, 200, or 300 mg/kg/day) of Gen. Gen- and Cr-treated rats exhibited increased immunoreactivity of Kim-1, RPA-1, and RPA-2 largely in the S1/S2 segments and to a lesser extent in the S3 segments of the proximal tubule of the kidney, whereas Hg-treated rats showed increased immunoreactivity of Kim-1, RPA-1, and RPA-2 in the S3 segments. Up-regulation of Kim-1, RPA-1, and RPA-2 expression correlated with injured tubular epithelial cells and also correlated with immunoreactivity of iNOS and nitrotyrosine. It is possible that iNOS activation with nitrotyrosine production in injured nephron segments may be involved in the induction of Kim-1, RPA-1, and RPA-2 following exposure to nephrotoxicants.     

Pathological changes in rats receiving cyclosporin A at immunotherapeutic dosage for 7 weeks.

In rats given an immunotherapeutic dose (25 mg/kg orally each day for 7 weeks) of cyclosporin A (Cy A) characteristic drug-induced pathological changes were observed, including impaired liver function, renal proximal tubular cell damage, progressive lymphopenia, lymphocyte depletion in lymphoid organs and marrow hypoplasia. Several additional and previously unreported features of Cy A toxicity were also demonstrated. The changes in renal and hepatic function were biphasic with temporary improvement during the course of the study. The most striking liver damage was in the form of a granulomatous hepatitis and a hypochromic microcytic anaemia developed in all experimental animals.     

Protective effect of melatonin and sodium thiosulphate on histopathology and ultrastructure of the kidney in rats with acute paraquat poisoning

Paraquat (PQ) toxicity produces severe injures in many major organs systems, including kidney, developing renal failure with fatal evolution in most of the cases. Several antidotes have been used in the treatment of paraquat intoxication without satisfactory results. The antioxidative effect of melatonin (MLT) and sodium thiosulphate (STS) on kidney in rats with acute intoxication by PQ was studied. Forty male Wistar rats were used, divided in 4 groups of 10 rats each. Group I, control, was injected intraperitoneally (ip) with 1 ml of saline solution; group II, received DL50 of PQ, ip; groups III and IV, DL50 of PQ, and simultaneously the first dose of MLT (15 mg/kg, ip) or STS (1,5 g/kg, i.p.) respectively. Thirty minutes later, groups III and IV received a second similar dose of MLT and TSS. After 24 hours, rats were sacrificed with pentobarbital, and kidneys were extracted for morphological study. Light and electronic microscopy observations showed in group II morphological changes of acute tubular necrosis in proximal tubule in group II, similar findings, with lesser magnitude, were observed in the animals treated with the antidotes, suggesting a partial protection. In conclusion, individual use of MLT and STS at the doses and time used partially prevent damage caused by paraquat to the cell. In consequence, more experiments with these drugs are necessary to considere them as specific treatments in cases of poisoning by paraquat.     

Effects of the calcium-channel blocker diltiazem on gentamicin-induced nephrotoxicity in rats

Injection of diltiazem (40 mg/kg/d) to gentamicin (75 mg/kg/d = G 75 or 100 mg/kg/d = G 100) treated rats enhances aminoglycoside-induced nephrotoxicity. As a result of this combination, acute renal failure becomes systematic and is often irreversible. The lesion is of tubular origin and is characterized by a large increase in the urinary N-acetyl-beta-D-glucosaminidase (u-NAG) activity and its NAG-B isoenzyme level. The phenomenon is twice as marked with G 75 (u-NAG x 6.8, NAG-B x 2.2) as with G 100 (u-NAG x 3.1, NAG-B x 1.1). The effect seems to be attenuated if diltiazem is administered as a preventive treatment or in drinking water. As well as its diuretic properties, diltiazem may aggravate the renal toxicity of gentamicin by reducing the proximal tubular availability of calcium. Diltiazem inhibits reabsorption and behaves like a non-competitive inhibitor of calcium. This deficiency favours the proximal tubular binding and the non-specific penetration of gentamicin in the cytosol and cellular organelles (microsomes, mitochondria). The tubular toxic symptoms which ensure (inactivation of membranaceous enzyme, reduction of microsomal protein synthesis and ATP level, decreased of solute reabsorptive flux) lead in turn to proximal tubular necrosis and acute renal failure.     

The use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis to detect renal damage in Sprague-Dawley rats treated with gentamicin sulfate.

Renal toxicity is a common manifestation to the exposure of laboratory animals and humans to a wide range of xenobiotics. Traditional methods for evaluating renal damage by clinical chemistry such as blood urea nitrogen (BUN) and serum creatinine are not sensitive to early, mild changes. The use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to measure the molecular weight spectrum of urinary proteins allows for an evaluation of the functional changes associated with renal damage. The ability of the kidney to filter and reabsorb proteins is related to the functional ability of glomeruli and the proximal tubules. Gentamicin sulfate produces injury to the S-1 and S-2 segments of the proximal tubule in laboratory animals and humans. While severe damage to the tubules is associated with increased BUN, serum creatinine, and N-acetyl-beta-glucosiminadase (NAG), mild injury is not detected by these means. The evaluation of urinary proteins by SDS-PAGE demonstrated renal toxicity at a dose of 6 mg/kg after 2 days of sc treatment. The NAG: creatinine ratio was shown to be elevated after 2 days of treatment at 63 mg/kg. The use of SDS-PAGE as described in this paper provides a sensitive method for detecting renal injury.