Physical Training Is a Potential Modifier of Risk for Contrast-Induced Acute Kidney Injury in Diabetes Mellitus.

BACKGROUND: Iodinated contrast (IC) is a leading cause of hospital-based acute kidney injury (AKI). Contrast-induced acute kidney injury (CI-AKI) is a decline in renal function due to iodinated contrast administration and occurs more frequently in individuals with increasingly common risk factors, such as diabetes mellitus (DM). Physical training (PT) can have renoprotective effects on CI-AKI in diabetic nephropathy. The aim of this study was to evaluate the injury in kidneys of diabetic rats submitted to treatment with IC, evaluating the impact of PT on hemodynamics and renal function in addition to oxidative profile in diabetic rats submitted to IC-AKI. MATERIALS AND METHODS: Adult male Wistar rats are randomized into four groups: citrate (n = 7): control group, citrate buffer (streptozotocin-STZ vehicle), intravenous tail (iv), single dose; DM (n = 7): STZ, 60 mg/kg, iv, single dose; DM+IC (n = 7): DM rats treated with IC (sodium meglumine ioxithalamate, 6 mL/kg, intraperitoneal (ip), single dose); DM+IC+PT (n = 7): DM rats treated with IC as mentioned and submitted to physical training. Renal function parameters (inulin clearance, neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine, and urinary albumin), hemodynamics (renal blood flow and renal vascular resistance), and oxidative profile (urinary peroxides, urinary TBARS, urinary nitric oxide, and renal tissue thiols) were evaluated. RESULTS: It was possible to observe a decrease in inulin clearance, renal blood flow, and thiols in renal tissue accompanied by an increase in urinary flow, serum creatinine, urinary albumin, renal vascular resistance, urinary peroxides, urinary nitrate, and TBARS in the DM group compared to the citrate group. The DM+IC group showed a reduction in inulin clearance, and the renal dysfunction was also seen by the increased NGAL. Renal hemodynamics and oxidative profile compared were also worsened in the DM group. PT improved renal function by increasing renal blood flow and thiol levels in renal tissue and reduced renal vascular resistance, metabolites of reactive oxygen, nitrogen species, and lipid peroxidation in the DM+IC+PT group compared to DM+IC. CONCLUSIONS: Our results confirmed that DM induction increases renal vulnerability to the toxicity of IC and an association between DM with IC predisposes to severe AKI with reduced renal function alongside with renal hemodynamic alterations and oxidative mechanism of injury. The PT showed a renoprotective effect in DM animals subjected to damage with IC by modulating renal hemodynamics and oxidative profile, confirming a potential to modify the risk of CI-AKI when diabetes mellitus is present.

Ascorbylperoxide Contaminating Parenteral Nutrition Is Associated With Bronchopulmonary Dysplasia or Death in Extremely Preterm Infants.

BACKGROUND: Ascorbylperoxide (AscOOH) is a hydrogen peroxide-dependent by-product of ascorbic acid that contaminates parenteral nutrition. In a guinea pig model, it caused oxidized redox potential, increased apoptosis, and decreased alveolarization. AscOOH detoxification is carried out by glutathione peroxidase (GPX). We hypothesize that extremely preterm infants have limited capacity for AscOOH detoxification. Our objective was to determine if there is an association between an early level of urinary AscOOH and later development of bronchopulmonary dysplasia (BPD) or death. MATERIALS AND METHODS: This prospective cohort study included 51 infants at <29 weeks of gestation. Baseline clinical characteristics and clinical outcomes data were collected. Urine samples were collected on days 3, 5, and 7 of life for urinary AscOOH. Blood samples on day 7 were collected for total plasma glutathione, GPX, and glutathione reductase. χ2, Student's t test, Spearman correlation ( r), linear regression (adjusted r2), and repeated-measure analysis of variance were used as appropriate. P < .05 was considered significant. RESULTS: Urinary AscOOH increased over time ( P = .001) and was higher in infants who later developed BPD or died ( P = .037). Compared with adults and full-term infants, total plasma glutathione concentration was low (median, 1.02 µmol/L; 25th-75th percentiles, 0.49-1.76 µmol/L), whereas GPX and glutathione reductase activities were sufficient (3.98 ± 1.25 and 0.36 ± 0.01 nmol/min/mg of protein, respectively). CONCLUSION: Extremely preterm infants have low glutathione levels, which limit their capacity to detoxify AscOOH. Higher first-week urinary AscOOH levels are associated with an increased incidence of BPD or death.

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats.

OBJECTIVE: The objective of this study was to evaluate the role of oxidative stress in an experimental model of streptozotocin-induced diabetic nephropathy in rats. MATERIALS AND METHODS: Wistar, adult, male rats were used in the study. Animals were divided in the following groups: Citrate (control, citrate buffer 0.01M, pH 4.2 was administrated intravenously - i.v - in the caudal vein), Uninephrectomy+Citrate (left uninephrectomy-20 days before the study), DM (streptozotocin, 65 mg/kg, i.v, on the 20th day of the study), Uninephrectomy+DM. Physiological parameters (water and food intake, body weight, blood glucose, kidney weight, and relative kidney weight); renal function (creatinine clearance), urine albumin (immunodiffusion method); oxidative metabolites (urinary peroxides, thiobarbituric acid reactive substances, and thiols in renal tissue), and kidney histology were evaluated. RESULTS: Polyphagia, polydipsia, hyperglycemia, and reduced body weight were observed in diabetic rats. Renal function was reduced in diabetic groups (creatinine clearance, p < 0.05). Uninephrectomy potentiated urine albumin and increased kidney weight and relative kidney weight in diabetic animals (p < 0.05). Urinary peroxides and thiobarbituric acid reactive substances were increased, and the reduction in thiol levels demonstrated endogenous substrate consumption in diabetic groups (p < 0.05). The histological analysis revealed moderate lesions of diabetic nephropathy. CONCLUSION: This study confirms lipid peroxidation and intense consumption of the antioxidant defense system in diabetic rats. The association of hyperglycemia and uninephrectomy resulted in additional renal injury, demonstrating that the model is adequate for the study of diabetic nephropathy.

The role of oxidative stress in streptozotocin-induced diabetic nephropathy in rats

ABSTRACT Objective The objective of this study was to evaluate the role of oxidative stress in an experimental model of streptozotocin-induced diabetic nephropathy in rats. Materials and methods Wistar, adult, male rats were used in the study. Animals were divided in the following groups: Citrate (control, citrate buffer 0.01M, pH 4.2 was administrated intravenously - i.v - in the caudal vein), Uninephrectomy+Citrate (left uninephrectomy-20 days before the study), DM (streptozotocin, 65 mg/kg, i.v, on the 20th day of the study), Uninephrectomy+DM. Physiological parameters (water and food intake, body weight, blood glucose, kidney weight, and relative kidney weight); renal function (creatinine clearance), urine albumin (immunodiffusion method); oxidative metabolites (urinary peroxides, thiobarbituric acid reactive substances, and thiols in renal tissue), and kidney histology were evaluated. Results Polyphagia, polydipsia, hyperglycemia, and reduced body weight were observed in diabetic rats. Renal function was reduced in diabetic groups (creatinine clearance, p < 0.05). Uninephrectomy potentiated urine albumin and increased kidney weight and relative kidney weight in diabetic animals (p < 0.05). Urinary peroxides and thiobarbituric acid reactive substances were increased, and the reduction in thiol levels demonstrated endogenous substrate consumption in diabetic groups (p < 0.05). The histological analysis revealed moderate lesions of diabetic nephropathy. Conclusion This study confirms lipid peroxidation and intense consumption of the antioxidant defense system in diabetic rats. The association of hyperglycemia and uninephrectomy resulted in additional renal injury, demonstrating that the model is adequate for the study of diabetic nephropathy.

Urinary and glomerular podocytes in patients with chronic kidney diseases.

BACKGROUNDS: Podocytes are highly differentiated epithelial cells involved in glomerular filtration. This study determines the clinical and histological significance of podocyte detachment and excretion in urine in patients with chronic kidney diseases. METHODS: Renal biopsy was performed in 59 patients (30 males, 29 females; mean age 48 ± 2 years), including 24 patients with immunoglobulin (Ig)A nephropathy, six each with focal segmental glomerulosclerosis, membranous nephropathy, and minimal change nephrotic syndrome, and 17 with other renal disorders. The number of glomerular podocytes and severity of morphological damage were evaluated in renal biopsy samples. Urinary podocytes were detected by anti-human podocalyxin antibody. The urinary IgG/albumin ratio and urinary peroxide products were assessed by gel electrophoresis and the 2',7'-dichlorodihydrofluorescein-diacetate method, respectively. RESULTS: A decrease in glomerular podocytes was associated with age (r = -0.33; P < 0.05), glomerulosclerosis (r = -0.43; P < 0.01), tubulointerstitial lesions (r = -0.46; P < 0.01), and low estimated glomerular filtration rates (r = 0.32; P < 0.05). Increased urinary podocyte excretion correlated with proteinuria (r = 0.36; P < 0.01), and was observed more frequently in patients with active histological lesions. Podocyte loss correlated with lower selectivity of proteinuria in patients with minimal change nephrotic syndrome and focal segmental glomerulosclerosis (r = -0.90; P < 0.001). Moreover, urinary peroxide products increased in association with glomerulosclerosis (r = 0.39; P < 0.05). CONCLUSIONS: Urinary podocyte excretion reflects ongoing glomerular injury in various kidney diseases, and podocyte loss correlated with glomerulosclerosis and impaired selectivity of proteinuria.

Ascorbylperoxide contaminating parenteral nutrition perturbs the lipid metabolism in newborn guinea pig.

The light exposure of parenteral nutritive solutions generates peroxides such as H(2)O(2) and ascorbylperoxide [2,3-diketo-4-hydoxyperoxyl-5,6-dihydroxyhexanoic acid]. This absence of photoprotection is associated with higher plasma triacylglycerol (TG) concentration in premature infants and oxidative stress and H(2)O(2)-independent hepatic steatosis in animals. We hypothesized that ascorbylperoxide is the active agent leading to high TG. The aim was to investigate the role of ascorbylperoxide in glucose and lipid metabolism in an animal model of neonatal parenteral nutrition. Three-day-old guinea pigs received through a catheter in the jugular solutions containing dextrose plus 0, 90, 225, or 450 microM ascorbylperoxide. After 4 days, blood and liver were sampled and treated for determinations of TG, cholesterol, markers of oxidative stress (redox potential of glutathione and F(2alpha)-isoprostane), and activities and protein levels of acetyl-CoA carboxylase (ACC), glucokinase, and phosphofructokinase (PFK). Ascorbylperoxide concentration was measured in urine on the last day. Data were compared by analysis of variance (p < 0.05). Plasma TG and cholesterol and hepatic PFK activity increased (200% of control), whereas ACC activity decreased (66% of control) in the function of the amount of ascorbylperoxide infused. Both markers of oxidative stress were higher in animals receiving the highest amounts of ascorbylperoxide. The logarithmic relations between urinary ascorbylperoxide and plasma TG (r(2) = 0.69) and hepatic PFK activity (r(2) = 0.26) were positive, whereas they were negative with ACC activity (r(2) = 0.50). In conclusion, ascorbylperoxide contaminating parenteral nutrition stimulates glycolysis, allowing higher availability of substrates for lipid synthesis. The logarithmic relation between urinary ascorbylperoxide and plasma TG suggests a very low efficient concentration.

A randomized controlled trial on parenteral nutrition, oxidative stress, and chronic lung diseases in preterm infants.

OBJECTIVES: To evaluate the effect of trace elements (TEs), when added to total parenteral nutrition (TPN) solutions, on peroxides load, and to test the hypothesis that protection of TPN from light can decrease peroxides load and is associated with improvement in oxidant-related clinical outcomes in preterm infants. SUBJECTS AND METHODS: A total of 80 preterm infants were randomized to 1 of 4 groups (n=20 each): group 1 received a mixture of dextrose and amino acids; group 2 received a mixture of dextrose, amino acids, and lipid emulsion; group 3 received dextrose, amino acids, lipid emulsion, and multivitamins (MVP); and group 4 received dextrose, amino acids, lipid emulsion, MVP, and TEs. Each group was subdivided into photo-protected and photo-exposed subgroups (n=10 each). Using ferrous oxidation of xylenol orange technique, we measured the baseline level of excreted urinary peroxides before and 48 hours after starting TPN. We examined the association among light protection, urinary peroxides, and clinical outcomes of these infants. RESULTS: Baseline urinary peroxides ranged between 5.5 and 24.8 micromol/L. A significant increase in urinary peroxides was observed in all groups after receiving TPN. The use of TEs did not affect peroxide production. In regression analysis, the addition of MVP (P<0.0001) and the exposure to light (P=0.02) were significantly associated with increased urinary peroxides. In the overall population, light exposure was associated with a significant increase in the incidence of chronic lung disease (adjusted OR 9.26, confidence interval 1.2-73; P=0.03) but had no effect on mortality, necrotizing enterocolitis, or sepsis. CONCLUSIONS: TEs in TPN solutions have no effect on the production of urinary peroxides. Addition of MVP and exposure of TPN to light are the 2 major sources of peroxides in TPN. Protection from ambient light is associated with a decrease in chronic lung disease.

Hydration and N-acetylcysteine in acute renal failure caused by iodinated contrast medium: an experiment with rats.

BACKGROUND: The involvement of nephrotoxic agents in acute renal failure (ARF) has increased over the last few decades. Among the drugs associated with nephrotoxic ARF are the radiologic contrast media whose nephrotoxic effects have grown, following the increasing diagnostic use of these agents. METHODS: We evaluated the effect of iodinated contrast (IC) medium, administered in combination, or not, with hyperhydration or N-acetylcysteine (NAC), on creatinine clearance, production of urinary peroxides and renal histology of rats. Adult Wistar rats treated for 5 days were divided into the following groups: control (saline, 3 ml/kg/day, intraperitoneally [i.p.]), IC (sodium iothalamate meglumine, 3 ml/kg/day i.p.), IC + water (12 mL water, orally + IC, 3 ml/kg/day i.p. after 1 hour), IC + NAC (NAC, 150 mg/kg/day, orally + IC, 3 ml/kg/day i.p. after 1 hour) and IC + water + NAC. RESULTS: IC medium reduced renal function, with maintenance of urinary flow. Hyperhydration did not reduce the nephrotoxic effect of the IC agent, which was observed in the group IC + NAC. The combination of hyperhydration and NAC had no superior protective effect compared with NAC alone. An increase in urinary peroxides was observed in the IC group, with NAC or water or the combination of both reducing this parameter. Histopathologic analysis revealed no significant alterations. CONCLUSIONS: In summary, given 5 days previously, NAC was found to be more effective than hyperhydration alone in the prevention of contrast-induced acute renal failure.

Decreased oxidative stress index of urine in patients with urinary tract infection.

AIM: To investigate the oxidative and antioxidative status of urine and serum of patients with urinary tract infection (UTI) and to compare them with those of controls. MATERIALS AND METHODS: The antioxidative status of urine and serum were evaluated by measuring total antioxidant capacity (TAC) and plasma vitamin C concentration. The oxidative status of the samples was assessed by measuring the total peroxide and the oxidative stress index (OSI) levels. The means of the parameters were compared and the relationships among them were determined. RESULTS: Total peroxide and OSI levels were found to be lower and TAC was found to be higher in the urine of patients with UTI. On the contrary, while the plasma vitamin C concentration and TAC of serum was lower, the total peroxide and OSI levels were higher in patients than controls. There was a negative correlation between serum TAC and urine TAC values. There was also a positive correlation between plasma vitamin C concentration and serum TAC levels. CONCLUSION: The urine of the patients with UTI have higher TAC and lower total peroxide and OSI levels. However, lower TAC and plasma vitamin C concentration and higher total peroxide and OSI levels were observed in UTI. This condition may be a factor which facilitates the development of the infection or is secondary to UTI.

Urinary metabolites of oxidative stress and nitric oxide in preterm and term infants.

BACKGROUND: Many neonatal diseases have been associated with oxidative stress and altered nitric oxide status. OBJECTIVE: To determine the effects of clinical interventions on the levels of urinary peroxides, a marker of oxidative stress, and urinary nitrate/nitrites, indices of nitric oxide production and metabolism, in the first 72 h of life in premature infants. METHODS: A single, spot urine sample was collected from 82 premature and 20 healthy term infants within the first 72 h of life. The peroxide levels were quantified using a fluorometric method, and nitrate/nitrite levels were quantified by chemiluminescence. RESULTS: Premature infants had a median peroxide level of 10.0 micromol/mmol creatinine (Cr) (interquartile range 4.8-20.0 micromol/mmol Cr). These values were significantly higher than term infants (median 5.0 micromol/mmol Cr, interquartile range 2.7-10.0 micromol/mmol Cr). Urinary nitrate/nitrite levels were not significantly different between preterm (220.5 micromol/mmol Cr, interquartile range 161-287 micromol/mmol Cr) and healthy term infants (244 micromol/mmol Cr, interquartile range 194-316 micromol/mmol Cr). For urinary peroxides, infants on TPN had significantly higher urinary peroxide levels than infants who were not on TPN at the time of urine collection (p = 0.006). Administration of indomethacin was associated with lower levels of urinary nitrate/nitrites (p = 0.0003). Both effects remained significant after controlling for gestational age, degree of respiratory distress and day of urine collection. CONCLUSION: Monitoring the level of both peroxides and nitrate/nitrite may offer added information about the degree of oxidative stress experienced by a newborn but needs to account for clinical and therapeutic interventions.

Multivitamin solutions for enteral supplementation: a source of peroxides.

OBJECTIVE: We investigated whether solutions of enteral vitamin supplementation are involved in the generation of peroxides and whether that contamination is biologically significant. METHODS: Peroxide contents of oral multivitamin preparations were measured over 3 wk after the initial opening of the containers. In selected premature infants (younger than 35 wk gestation), urinary peroxides were measured after initiating oral multivitamin supplementation. RESULTS: Peroxides in multivitamin solutions for enteral use are predominantly organic peroxides because they resist catalase. After the initial opening of the containers, there was a two-fold increase in total peroxides levels (P < 0.05) even in the preparation without riboflavin, a catalyst for the generation of peroxides. Initiation of oral vitamin supplementation was associated with increased (P < 0.05) urine peroxide levels. The high organic peroxide load did not correlate with its urinary excretion, mostly in the form of H(2)O(2). The excretion of H(2)O(2) corresponded to its oral intake from the multivitamin solution. CONCLUSIONS: Compared with parenteral multivitamin solutions, the enteral preparations contained higher organic peroxide levels starting with the initial opening of the bottles. The increased urinary excretion of H(2)O(2) after enteral multivitamin supplementation suggested a systemic diffusion of peroxides or of components of the multivitamin preparation responsible for the generation of peroxides. This oxidant load was not quenched by the immature antioxidant defenses of premature infants.

Photoprotection of solutions of parenteral nutrition decreases the infused load as well as the urinary excretion of peroxides in premature infants.

Light exposure and multivitamins are contributing factors to the generation of peroxides in solutions of parenteral nutrition. This article verifies if peroxides infused with parenteral nutrition are of biological significance in neonates. The mechanisms responsible for the generation of peroxides in total parenteral nutrition solutions are reviewed. The consequences of infused peroxides on an index of oxidant stress and on levels of a central antioxidant are evaluated in an animal model. The effect of photoprotection of parenteral nutrition on a biological marker of redox imbalance is evaluated in the urine of premature infants. Parenteral multivitamins produce a drop in glutathione and an oxidant stress similar to peroxides in the lungs of newborn guinea pigs. Infused peroxides elicited an increased urinary peroxide excretion in infants receiving parenteral nutrition exposed to light. Photoprotection reduced levels of infused and excreted peroxides. The results suggest that peroxides infused with total parenteral nutrition are not fully quenched by premature infants.

Increased urinary peroxides in newborn infants receiving parenteral nutrition exposed to light.

OBJECTIVES: To determine whether peroxide loads infused with total parenteral nutrition (TPN) are fully quenched by premature infants. STUDY DESIGN: After baseline urine peroxide levels were established, the effect of various parenteral regimens was correlated with urinary peroxide levels in 64 newborn infants

The metabolism of ethylbenzene hydroperoxide in the rat.

Ethyl[14C]benzene hydroperoxide administered orally to female rats (30 mg/kg) is rapidly absorbed and metabolized. Most of the administered compound (81%) is eliminated in the 0-24 h urine. Major metabolites include mandelic acid (23%), hippuric acid (34%) and 1-phenylethyl glucuronide (4%). Ethyl[14C]benzene is metabolized via 1-phenylethanol to the same mixture of metabolites as obtained with the hydroperoxide. Biotransformations of the hydroperoxide and their likely biochemical mechanisms are discussed.