Ultrastructural Changes in the Kidney of Rats with Acute Exposure to Cadmium and Effects of Exogenous Metallothionein

Ultrastructural changes in the kidneys of rats after acute cadmium exposure and the effects of exogenous metallothionein (MT) were studied by transmission electron microscopy. Thirty-six adult Wistar rats were divided into three groups. Cadmium chloride (CdCl₂) (3.5 mg/kg/day) was injected subcutaneously in the first group. In the second group, 30 μmol/kg MT was administered in addition to CdCl₂. Control rats received 0.5 ml subcutaneous saline solution. Four rats from each group were killed on days 1, 3, 5, and 7 after administration of the compounds. Kidney tissues were taken and fixed in 2.5% glutaraldehyde solution for electron microscopic observations. Tissue damage in kidney increased as time passed since the administration of CdCl₂ in the first group. Degeneration in the proximal and distal tubules was observed. Increased apoptosis was seen in the proximal tubules epithelium, especially on day 7. Peritubular capillaries became dilated, there was degeneration of the endothelial cells, and the amount of intertubular collagen fibers was increased. On day 1, irregular microvilli in the proximal tubules, deepening of the basal striations, and myelin figures; on day 3, multiple vesicular mitochondria and regions of edema around tubules; on days 5 and 7, increased apoptotic cell in the proximal tubules and widened rough endoplasmic reticulum of the endothelial cells of glomerular capillaries were observed. We observed that the structural alterations that increased depending on the day of Cd administration decreased after exogenous MT administration, the dilation of the peritubular capillaries persisted, and there were degenerated proximal tubules. It was established that cadmium chloride was toxic for kidney cortex and caused structural damage. Exogenous MT partly prevents CdCl₂-induced damage.     

THE EFFECTS OF LITHIUM ON ATPase ACTIVITY IN SUBCELLULAR FRACTIONS FROM RAT BRAIN

Abstract— The effects of lithium chloride in vitro and in vivo were investigated on Na-K ATPase and Mg ATPase activities in synaptic plasma membrane, mitochondrial and synaptic vesicle fractions prepared from rat brain. In vitro , lithium chloride (10⁻³-10⁻⁸ m ) had no effect on ATPase activity in any of the fractions studied. Lithium chloride given chronically by i.p. injection (30 mg/rat/day) for 9 days had little effect on synaptic plasma membrane ATPases. Dietary administration of lithium chloride (60 mmol/kg food) produced a small but significant increase in synaptic plasma membrane Mg ATPase activity after 3 weeks administration and mitochondrial Mg ATPase activity after 1 week. There was no effect on synaptic plasma membrane Na-K ATPase activity. Salt supplementation reduced the toxic effects of lithium administration and it is suggested that toxicity may account for some of the previously reported changes in synaptic membrane ATPases produced by lithium.     

Effects of lithium on the pituitary-gonadal axis in the rat: evidence for dose-dependent changes in plasma gonadotropin and testosterone levels

The purpose of the present study was to examine the effects of lithium, a drug which is now used rather widely in the treatment of acute mania and the prophylaxis of manic-depressive bipolar disorders, on the pituitary-gonadal function in the laboratory rat. Sexually adult male rats, maintained under standardized laboratory conditions (LD 14: 10; lights on at 06:00 h, CST), were injected (ip) with lithium chloride both acutely for 1 day and chronically for 5 days, and by utilizing a low and high dose. For the low dose, lithium was injected twice daily (at 10:00 and 15:00 h) at 2.5 meg/Kg for 1 and 5 days, whereas in the high dose groups, also receiving lithium twice daily and at the same hours, the dosages were 5 meq/Kg for 1 day and 3.5 meq/Kg for 5 days. Animals were sacrificed 4 hours after the last lithium (or saline) injections. Plasma and pituitary levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH), and plasma levels of testosterone (T) were measured by radioimmunoassay (RIA). The administration of the low dose led to a significantly higher (P less than 0.001) plasma FSH, but unaltered plasma LH, levels after 5 days. In contrast, the high dose lithium led to significant suppressions of plasma LH (P less than 0.02; on day 5) and FSH (P less than 0.001; on both day 1 and 5) levels. The levels of plasma T also showed a significant reduction following the low dose (P less than 0.02; on day 5), as well as the high dose lithium treatment, as evident after both 1 (P less than 0.02) and 5 (P less than 0.02) days. Regardless of the dosage, or the duration of treatment, pituitary gonadotropin levels remained unaltered following lithium. The results of our present experiments suggest that lithium administration, either acutely or on a chronic basis, might be associated with significant adverse effects on the pituitary-testicular axis. Furthermore, since some of the hormonal changes were evident when plasma lithium concentration was within the therapeutic range, our data may have potential clinical implications.     

Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat.

The model nephrotoxin gentamicin was administered to male Wistar-derived rats daily, for 7 days, at 60 mg kg-1 day-1, subcutaneously, twice daily. Conventional clinical chemistry urinalysis showed a significant increase in N-acetyl-beta-D-glucosaminidase (NAG) activity from day 3. At necropsy on day 9, clear histological damage to the kidney was noted with all animals showing a generally severe nephropathy primarily focused on the proximal convoluted tubules. The urinary excretion pattern of endogenous metabolites over the time course of the study was studied using a combination of 1H-NMR spectroscopy and HPLC-TOF-MS/MS using electrospray ionization (ESI). Changes in the pattern of endogenous metabolites as a result of daily administration of gentamicin were readily detected by both techniques with significant perturbations of the urinary profile observed from day 7 onwards. The findings by 1H-NMR included raised glucose and reduced trimethylamine N-oxide (TMAO). Changes in metabonomic profiles were observed by HPLC-MS in both positive and negative ESI. The MS data showed reduced xanthurenic acid and kynurenic acid, whilst neutral loss experiments also revealed a changed pattern of sulphate conjugation on gentamicin administration.     

Apoptosis in the cells of parenchymatous organs in subacute sodium nitrate poisoning

Subacute intoxication was induced by the oral administration of sodium nitrate 200 mg/kg during 150 days to Wistar rats. After the time had been up severe damaging were found in liver, kidney, heart and thymic tissues. In the liver cells the DNA fragmentation in "scale" manner was found, but not in kidney and heart cells. Simultaneously, the Ca2+, Mg(2+)-depended endonucleases activity were increased in the liver nuclei extracts under intoxication. It was suggested that increasing of apoptosis in liver is the universal reaction to toxins.     

The role of testosterone in the regulation of P-glycoprotein functioning

The functional activity of P-glycoprotein (Pgp) was studied in Chinchilla rabbits after orchiectomy and administration of testosterone undecanoate after surgery. The functional activity of Pgp was determined by the pharmacokinetics of fexofenadine, its marker substrate. In addition, the localization of the transport protein was assessed in the liver, kidney, and jejunum by the immunohistochemistry. It was found that a decrease in the serum testosterone concentration after orchiectomy leads to an increase in Pgp activity on the 14th and 21st days after the surgery, which is accompanied by an increase in the staining intensity of Pgp-positive epithelium membranes of the proximal and distal renal tubules. It was found that the administration of testosterone at a dose of 6 mg/kg body weight in the period after the surgery neutralizes these changes.     

Housing conditions affect susceptibility to mercury in the golden hamster

Individually-housed and group-housed golden hamsters (Mesocricetus auratus), aged 8 weeks, were studied with regard to their susceptibility to a single gavage of mercuric chloride (10 mg/kg body weight). Body weight and food consumption were measured for 10 days (day -9 to day 0) in a pre-application period and for 13 days (day 1 to day 13) in a post-application period. Mercuric chloride administration significantly reduced body weight gain in both isolated and grouped hamsters at day 1 compared to vehicle controls. While the individually-housed treated hamsters recovered during the post-application period, the group-housed treated hamsters showed a reduced body weight gain over the whole post-application period. Results are discussed in relation to elevated susceptibility to intoxication in group-housed hamsters triggered by high social stress. This study highlights the need to carefully consider the housing conditions which can influence the results of teratological experiments.     

Distribution of histamine in the rat kidney during pregnancy and development

Summary An antiserum against conjugated histamine and two oligonucleotide probes that detect the mRNA encoding L-histidine decarboxylase (HDC) involved in histamine synthesis were used to study the appearance of histamine and its location in the kidneys of fetal, newborn and young postnatal rats and in the kidneys of pregnant rats. On embryonic days 16 and 18 (E16 and E18), some HA-immunoreactive (HA-ir) cells were found within the largest S-shaped bodies. Histamine was found to appear rapidly between the 18th and 20th embryonic days in the convoluted tubules of the kidneys. On postnatal day 0 (P0), the distal convoluted tubules and collecting ducts exhibited bright fluorescence, the intensity of which decreased quickly so that it was faint on day P4 and absent at later stages. In kidneys of pregnant rats HA-ir was found in the epithelium of both the Bowman's capsule, collecting ducts and in a few cells within the tubules. Nonuniform HA-ir was also detected within glomeruli. No evidence for the presence of L-histidine decarboxylase mRNA in kidneys of fetuses or pregnant rats was seen. It is concluded that distinct structures in the developing rat kidney contain histamine during a period around birth from day E20 to day P4. In the pregnant rat, the epithelium that is in direct contact with the urine flow is immunoreactive for histamine from day 16 to 20 of pregnancy. The results suggest that histamine is not synthesized locally in the kidneys but rather originates from other tissues.     

Severe lithium intoxication treated by forced diuresis.

In a woman who had been in coma for 4 days because of severe lithium intoxication forced diuresis led to full recovery. Forced diuresis is simpler than hemodialysis and may be as effective in some patients with severe lithium intoxication.     

Histochemical studies on the uptake of horseradish peroxidase by rat kidney slices

When rat kidney slices were incubated in the presence of horseradish peroxidase, there was an energy-dependent uptake of the protein by the cells of the kidney tubules. The uptake was greatest in the proximal convoluted tubules and in the thick ascending limbs of the loops of Henle; it was abolished by cold, anoxia, 2,4-dinitrophenol, and fluoroacetate, and was more readily depressed by unfavorable metabolic conditions in the proximal convoluted tubules than in the thick ascending limbs. Protein uptake was inhibited when the kidney slices were incubated in electrolyte-free media. In sodium chloride solutions, uptake was reduced as sodium was progressively replaced by choline, and ouabain inhibited uptake in the proximal convoluted tubules, but not in the thick ascending limbs. To a limited extent, lithium could replace sodium in the incubation medium with no depression of peroxidase uptake. These results suggest that a sodium-stimulated, ouabain-sensitive ATPase may be involved in the uptake of protein by cells of the kidney tubule. The intracellular transport of peroxidase in cells of the proximal convoluted tubules was abolished by cold, anoxia, and 2,4-dinitrophenol, but it was not affected by concentrations of ouabain which inhibited the uptake of the protein.     

Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat

Abstract

The model nephrotoxin gentamicin was administered to male Wistar-derived rats daily, for 7 days, at 60?mg?kg^?1?day^?1, subcutaneously, twice daily. Conventional clinical chemistry urinalysis showed a significant increase in N-acetyl-β-D-glucosaminidase (NAG) activity from day 3. At necropsy on day 9, clear histological damage to the kidney was noted with all animals showing a generally severe nephropathy primarily focused on the proximal convoluted tubules. The urinary excretion pattern of endogenous metabolites over the time course of the study was studied using a combination of ¹H-NMR spectroscopy and HPLC-TOF-MS/MS using electrospray ionization (ESI). Changes in the pattern of endogenous metabolites as a result of daily administration of gentamicin were readily detected by both techniques with significant perturbations of the urinary profile observed from day 7 onwards. The findings by ¹H-NMR included raised glucose and reduced trimethylamine N-oxide (TMAO). Changes in metabonomic profiles were observed by HPLC-MS in both positive and negative ESI. The MS data showed reduced xanthurenic acid and kynurenic acid, whilst neutral loss experiments also revealed a changed pattern of sulphate conjugation on gentamicin administration.     

Cytoarchitectural alterations in kidney of Wistar rat after oral exposure to cadmium chloride

Male Wistar rats were randomly divided into three groups - A, B and C. A dose of 5 mg and 10 mg of cadmium chloride/kg body weight/day was orally administered to groups B and C, respectively. Rats from group A served as control. Rats were sacrificed on 1st, 2nd, 4th, 6th, and 8th week after initiation of the experiment. Kidneys were removed immediately, fixed in Bouin's fixative, routinely processed and stained with hematoxylin and eosin. The present study showed that the histopathological changes were caused in kidney of rats by cadmium exposure. The changes noticed were mainly - the glomerular swelling (at initial stage), the shrinkage of glomerulus (at later stage), the tubular dilatation, hypertrophy of tubular epithelium, degeneration of glomerulus and renal tubules and deposition of eosin-positive substances in the glomerulus and renal tubules. However, lesions were depended upon the doses and duration of the treatment.     

Intrarenal transfer of an intracellular fluorescent fusion of angiotensin II selectively in proximal tubules increases blood pressure in rats and mice

The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT(1) (AT(1a)) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney (P < 0.01) and more than threefold in proximal tubules (P < 0.01), but remained unchanged in plasma or urine. Systolic blood pressure was increased in ECFP/ANG II-transferred rats by 28 ± 6 mmHg (P < 0.01), whereas fractional sodium excretion was decreased by 20% (P < 0.01) and fractional lithium excretion was reduced by 24% (P < 0.01). These effects were blocked by losartan and prevented in AT(1a) knockout mice. Transfer of a scrambled ECFP/ANG IIc had no effects on blood pressure, kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT(1a) receptors and increasing sodium reabsorption in proximal tubules.     

Lithium effect on testicular tissue and spermatozoa of viscacha (Lagostomus maximus maximus). A comparative study with rats.

We investigated the effect of lithium chloride administration (Sigma): 1 mmol/kg b.w. i.p./day for 35 days on the testes and sperm of viscacha (Lagostomus maximus maximus), a nocturnal rodent found only in the pampas of Argentina. The histological study showed that hypospermatogenesis and the sperm number per mL decreased markedly in comparison with the controls (treatment group: 315 x 10(6) +/- 77 x 10(6); control group: 693 x 10(6) +/- 39 x 10(6), Means +/- SEM, Student's t-test: p < 0.05). The sperm motility and viability were also affected. Under the same treatment, the testicular tissue and the sperm of rats were not damaged. Moreover, lithium induced these changes when the plasm levels were within the therapeutic range in humans. Our results provide evidence for the claim that viscacha testes and sperm react very sensitively to low doses of lithium, whereas these concentrations do not produce damage in rats.     

Bradykinin potentiating factor isolated from Buthus occitanus venom has a protective effect against cadmium-induced rat liver and kidney damage

Bradykinin and its related peptides are widely distributed in venomous animals, including scorpion. A peptide fraction isolated from the venom of the Egyptian scorpion Buthus occitanus was proved to have a bradykinin-potentiating activity. The aim of the present study was conducted to investigate whether the treatment with bradykinin potentiating factor (BPF) offers more beneficial effects in reversing cadmium-induced oxidative stress in rat liver and kidney. Adult male rats, equally divided into control and two treated groups, 10 animals in each group. group (I) was orally given (1 ml) saline and served as a control group; group (II) of rats was given cadmium chloride (4 mg/kg) alone, once daily an oral dose for 7 successive days; group (III) of rats was given ip injection (1 ml) BPF, once daily a dose for 7 successive days prior to CdCl₂ treatment and on the next 7 successive days with the same dose of cadmium as group II. Both organs were subjected to histopathological analysis with the light microscope. The activities of alanine aminotransferase (ALT), asparate aminotransferase (AST) and alkaline phosphatase (ALP) in serum were measured as indicators of the liver function. As parameters of the kidney function, creatinine, uric acid and urea concentrations in serum were determined. Also, malondialdehyde (MDA), reduced glutathione (GSH), super oxide dismutase (SOD) and catalase (CAT) were determined in both tissues. Cd exposure caused a significant decrease or inhibition in the activities of GSH, SOD, and CAT, with significant increase in the level of MDA, in versus to control groups in both liver and kidney. Also, when Cd was treated in co-administration with BPF induced increase or stimulation in the activity of GSH, SOD, and CAT, with significant decrease in the level of MDA when compared to Cd group in both organs. Histopathological changes of liver and kidney were also in accordance with the biochemical findings. Our data showed that Cd treatment induced histopathological alteration in the liver, severe hydropic degeneration in centrolobular zones. Inflammatory cells infiltration around the congested central vein and an obvious injury in some renal tubules. Bradykinin potentiating factor (BPF) administration prevented the histopathological alterations which observed in Cd-groups and both liver and kidney had essentially normal appearance in histopathological examination. In conclusion, BPF markedly ameliorated cadmium-induced liver and kidney tissue damage as evidenced by histological and biochemical examinations and acts as a potent scavenger of free radicals to protect the liver and kidney against the deleterious effect of acute cadmium intoxication.     

beta-adrenergic responsiveness of rats treated chronically with isoproterenol

The effect of chronic administration of isoproterenol on isoproterenol-induced thirst and isoproterenol-induced changes in heart rate and selected organ weights of male rats was studied. Administration of 25 micrograms isoproterenol/kg, s.c., in saline daily for 10 days was accompanied by a significant attenuation of the characteristic increase in water intake following a challenging dose of isoproterenol (25 micrograms/kg, s.c.) on the 11th day. Administration of 25 micrograms isoproterenol/kg, s.c., every 2nd, 3rd or 4th day for 10 days was without significant effect on water intake following isoproterenol (25 micrograms/kg, s.c.) on the 11th day. Administration of 25 micrograms isoproterenol/kg, s.c., every day for 10 days led to a slight increase in cardiac responsiveness to a challenging dose of isoproterenol (25 micrograms/kg) on the 11th day. Chronic treatment with this low dose of isoproterenol for 10 days was also accompanied by a significant increase in the ratio of heart weight to body weight but no significant changes in the ratio of kidney, adrenal, thyroid, spleen, or interscapular brown fat to body weight. Thus, daily administration of the beta-adrenergic agonist isoproterenol for 10 days can alter beta-adrenergic responsiveness in the rat with beta 1 (heart rate) and beta 2 (thirst) mediated responses showing opposite effects. In addition, the results suggest that tests of beta-adrenergic responsiveness must be assessed in terms of the frequency of administration of the agonist.     

Effect of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one on reproductive organs of the male laboratory mouse

The effect of subcutaneous administration (10, 15 and 20 mg/kg body weight/day, for 21 days; and 20 mg/kg body weight/day, for 28 days) of 17 alpha-cyanomethyl-17 beta-hydroxy- estra-4, 9-dien-3-one (STS 557) on the male reproductive organs of the Parkes strain mouse was investigated. The effect of the treatment on the testis was not uniform; both regressed and normal seminiferous tubules were observed in the same section of the organ. Furthermore, the histological changes observed in the seminiferous tubules in testes of STS 557--treated mice were not different in different dosage groups. In general, in moderately affected seminiferous tubules, the germinal epithelium was thin and consisted of Sertoli cells, spermatogonia, spermatocytes and spermatids; such tubules showed presence of many vacuoles in the epithelium. In severe cases, the tubules had collapsed and were lined by mainly Sertoli cells, spermatogonia and spermatocytes. The treatment also caused marked depression in motility and concentration of spermatozoa in cauda epididymidis, weight of accessory sex glands and in the levels of sialic acid and fructose in the epididymis and seminal vesicle, respectively. By 56 days of drug withdrawal, the alterations induced in the reproductive organs returned to control levels, suggesting that STS 557 treatment induces reversible alterations in the male reproductive organs of Parkes strain mouse.     

Ontogeny of calbindin-D28K and calretinin in developing chick kidney

The ontogeny of two calcium-binding proteins (calbindin-D_28k and calretinin) was studied by immunohistochemical techniques in developing chick kidney. This study showed the presence of calbindin on the 5th incubation day and calretinin on the 7th incubation day in mesonephric distal and connecting tubules, and in the medial wall of the Wolffian duct. At later stages, immunostaining for these two proteins, in particular for calretinin, was also demonstrated in some metanephric proximal tubules. Glomeruli and Bowman's capsules were negative both in the mesonephros and metanephros. The presence of calretinin in the developing kidney has thus been demonstrated for the first time. The early expression of calbindin and calretinin in mesonephric distal tubules suggests their role in regulating the final excretion of calcium. The different patterns of immunoreactivity of the walls of the Wolffian duct can be correlated with their different histogenetic and histological features.     

Targeting Superoxide Dismutase to Renal Proximal Tubule Cells Attenuates Vancomycin-induced Nephrotoxicity in Rats

Vancomycin hydrochloride (VCM), a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). As it is known to induce renal dysfunction, the dose and the duration of its administration are limited. Moreover, the mechanism of VCM-induced renal dysfunction remains to be unclear. To evaluate the involvement of free radical on VCM-induced renal dysfunction, we carried out analysis with a hexamethylenediamine-conjugated superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Male Wistar rats (weighing 200-210 g) were intraperitonealy administered with 200 mg/kg of VCM twice a day for 7 days. AH-SOD 5 mg/kg/day was subcutaneously injected 5 min before every VCM injection. VCM induced renal injury dose-dependently. Biochemical analyses revealed that plasma levels of blood urea nitrogen and creatinine significantly increased in the VCM-treated group by an AH-SOD-inhibitable mechanism. VCM simultaneously elicited an increase of 8-OHdG levels and chemiluminescence intensity of free radical generation in the kidney. Histological examination revealed that VCM also elicited a marked destruction of glomeruli and necrosis of proximal tubules. AH-SOD inhibited these phenomena in the kidney. These results suggested that oxidative stress might underlie the pathogenesis of VCM-induced nephrotoxicity and targeting SOD and/or related antioxidants to renal proximal tubules might permit the administration of higher doses of VCM sufficient for eradication of MRSA without causing renal injury.     

Targeting superoxide dismutase to renal proximal tubule cells attenuates vancomycin-induced nephrotoxicity in rats

Vancomycin hydrochloride (VCM), a glycopeptide antibiotic, has a broad spectrum against methicillin-resistant Staphylococcus aureus (MRSA). As it is known to induce renal dysfunction, the dose and the duration of its administration are limited. Moreover, the mechanism of VCM-induced renal dysfunction remains to be unclear. To evaluate the involvement of free radical on VCM-induced renal dysfunction, we carried out analysis with a hexamethylenediamine-conjugated superoxide dismutase (AH-SOD) which rapidly accumulates in renal proximal tubule cells and inhibits oxidative injury of the kidney. Male Wistar rats (weighing 200-210 g) were intraperitonealy administered with 200 mg/kg of VCM twice a day for 7 days. AH-SOD 5 mg/kg/day was subcutaneously injected 5 min before every VCM injection. VCM induced renal injury dose-dependently. Biochemical analyses revealed that plasma levels of blood urea nitrogen and creatinine significantly increased in the VCM-treated group by an AH-SOD-inhibitable mechanism. VCM simultaneously elicited an increase of 8-OHdG levels and chemiluminescence intensity of free radical generation in the kidney. Histological examination revealed that VCM also elicited a marked destruction of glomeruli and necrosis of proximal tubules. AH-SOD inhibited these phenomena in the kidney. These results suggested that oxidative stress might underlie the pathogenesis of VCM-induced nephrotoxicity and targeting SOD and/or related antioxidants to renal proximal tubules might permit the administration of higher doses of VCM sufficient for eradication of MRSA without causing renal injury.