8-hydroxy-2--deoxyguanosine and Kidney-Failure--Chronic

Both the formation and reactions of hydroxyl radical (•OH) are quantitative chemical reactions even in mammalians, and so we can reproduce such in vivo reactions in test tubes. Daily urinary excretions of some reaction products have been used to estimate the amount of •OH produced daily. Although urinary 8-hydroxydeoxyguanosine (8-OHdG) is a well-known marker of •OH, we have shown that creatol (CTL: 5-hydroxycreatinine), an •OH adduct of creatinine (Crn), and its metabolite, methylguanidine (MG), are better markers, because the amount of •OH scavenged by deoxyguanosine (dG) in the body is negligible. We measured CTL and MG together with Crn in 24-h urine, and calculated their molar sum, CTL + MG, providing a daily estimate of moles of •OH scavenged with Crn, and, from the molar ratio (CTL + MG)/Crn, we can calculate the percentage of Crn that was used to scavenge •OH. Healthy subjects and normal rats were indicated to use circa (ca.) 0.2 and 0.3% of Crn in order to scavenge •OH, respectively, because the corresponding ratios, scavenged •OH/Crn, were 2.2 and 3.0 mmole/mole (24-h urine) (Crn scavenged ca. 20-25 μmole and ca. 200 pmole of •OH in healthy subjects and normal rats, respectively). Since 8-OHdG/Crn has been reported to be 1.9 μmole/mole (24-h urine), the daily scavenging capacity with Crn is 10(3)-fold more than dG. In patients with chronic renal failure (CRF) or chronic kidney disease (CKD) at stages 3-5: glomerular filtration rate (GFR) < 60 mL/min/1.73 m(2), •OH levels increased in proportion to the severity of CKD: up to ca. 3% of Crn was used daily in order to scavenge •OH. Although the accumulation of MG in organs has not been reported except for the brain and skin tissues in normal animals, •OH increases markedly and MG becomes detectable in all organs such as the kidney, liver, and heart in CRF rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Creatinine; Deoxyguanosine; Free Radical Scavengers; Glomerular Filtration Rate; Humans; Hydroxyl Radical; Kidney; Kidney Failure, Chronic; Methylguanidine; Predictive Value of Tests; Rats; Severity of Illness Index; Time Factors

In end-stage renal failure, genomic damage is enhanced. This has been shown both in the predialysis and dialysis phase by various biomarkers, such as micronuclei frequency and single cell gel electrophoresis in lymphocytes as well as with 8-hydroxy-2'-deoxyguanosine in leukocytes. There are also data about mitochondrial DNA deletions and chromosomal abnormalities. Genomic damage may be induced by a multitude of toxic factors and mutagens, in particular via enhanced generation of reactive oxygen species. In in vitro studies, incubation of tubular cells with various AGEs (carboxymethyllysine-BSA, AGE-BSA, and methylglyoxal-BSA) and angiotensin II resulted in a marked DNA damage. Coincubation with various antioxidants as well as the angiotensin II receptor blocker, candesartan, suppressed the toxic action. Moreover, an improved uremic state by daily hemodialysis ameliorated the genomic damage in lymphocytes, as compared to patients on conventional hemodialysis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Antioxidants; Chromosome Aberrations; Comet Assay; Deoxyguanosine; DNA Damage; DNA Repair; DNA, Mitochondrial; Gene Deletion; Glycation End Products, Advanced; Humans; Kidney Failure, Chronic; Micronuclei, Chromosome-Defective; Renal Dialysis; Sister Chromatid Exchange

AST-120 is an oral adsorbent that attenuates the progression of chronic renal failure (CRF) and improves the prognosis of the patients under dialysis. Although tubulointerstitial injury is more important than glomerulopathy in terms of renal prognosis in patients with CRF, effect of AST-120 on tubular injury in CRF patients remains unknown. In this study, we examined whether and how AST-120 treatment could improve tubular damage in nondiabetic CRF patients. Fifty nondiabetic CRF patients were enrolled in the present study and divided into 2 groups: one was the AST-120-treated group (15 men and 10 women) and the other was the age-, sex-, and clinical variables-matched non-AST-120-treated control group. Patients were followed up for 12 months. We investigated the effects of AST-120 on serum levels of interleukin-6 (IL-6), proteinuria, and urinary excretion levels of 8-hydroxydeoxyguanosine (8-OHdG) and L-fatty acid binding protein (L-FABP), markers of oxidative stress and tubular injury, respectively. AST-120 treatment (6 g/d), but not control treatment, for 12 months significantly reduced IL-6, proteinuria, and urinary excretion levels of L-FABP and 8-OHdG, and inhibited the increase in serum creatinine in CRF patients. In univariate analyses, L-FABP levels were correlated with age, proteinuria, 8-OHdG, and IL-6. In multiple stepwise regression analysis, proteinuria and urinary 8-OHdG levels were independently related to L-FABP levels (R² = 0.605). Our present study demonstrated for the first time that AST-120 improved tubular injury in nondiabetic CRF patients. AST-120 may exert beneficial effects in CRF patients by protecting tubular damage partly via reduction of proteinuria and oxidative stress generation.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adsorption; Aged; Biomarkers; Carbon; Creatinine; Deoxyguanosine; Disease Progression; Fatty Acid-Binding Proteins; Female; Humans; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Oxides; Proteinuria

Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia.. The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP--a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG--a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers.. After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period.. These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Aged; Arginine; Atherosclerosis; Biomarkers; Cardiovascular System; Carotid Intima-Media Thickness; Deoxyguanosine; Dose-Response Relationship, Drug; Erythropoietin; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Oxidative Stress; Prospective Studies; Recombinant Proteins; Treatment Outcome

Oxidative stress is accepted as a nonclassical cardiovascular risk factor in chronic renal failure patients. The aim of this study was to evaluate the relation between oxidative DNA damage (8-hydroxy-2'-deoxyguanosine/deoxyguanosine [8-OHdG/dG] ratio), oxidative stress biomarkers, antioxidant enzymes, and carotid artery intima-media thickness (CIMT) in hemodialysis (HD) patients. Forty chronic HD patients without known atherosclerotic disease and 48 age- and sex-matched healthy individuals were included in the study. Plasma malondialdehyde (MDA) levels and 8-OHdG/dG ratio were determined as oxidative stress markers. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as antioxidants. CIMT was assessed by carotid artery ultrasonography. 8-OHdG/dG ratios and MDA levels were higher; SOD and GPx activities were lower in HD patients compared to controls. HD patients had significantly higher CIMT compared to controls (0.61 ± 0.08 vs. 0.42 ± 0.05, p < 0.001). There was a significant positive correlation between CIMT and 8-OHdG/dG ratio (r = 0.57, p < 0.01) and MDA levels (r = 0.41, p < 0.01), while there was a significant negative correlation between CIMT and SOD (r = -0.47, p < 0.01) and GPx levels (r = -0.62, p < 0.01). It is firstly demonstrated that CIMT is positively correlated with oxidative DNA damage in HD patients without known atherosclerotic disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Atherosclerosis; Biomarkers; Carotid Artery Diseases; Deoxyguanosine; DNA Damage; Female; Glutathione Peroxidase; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Renal Dialysis; Risk Factors; Superoxide Dismutase

We examined the effects of 2 calcium channel blockers, benidipine (T-, L-, and N-type) and amlodipine (L- and N-type), on renal, inflammatory, oxidative, and atherosclerosis markers in hypertensive patients with mild chronic kidney disease (CKD).. Forty hypertensive patients with CKD were assigned randomly to either of the 2 treatments: 8 mg benidipine once daily (n = 20, group A) or 5 mg amlodipine once daily (n = 20, group B). Treatment was continued for 12 months. Blood pressure, serum creatinine, estimated glomerular filtration rate, urinary protein excretion, urinary liver-type fatty acid-binding protein, interleukin-6, high mobility group box-1 protein, urinary 8-hydroxy-2'-deoxyguanosine, pulse wave velocity, intima-media thickness, and blood asymmetric dimethylarginine were monitored.. Blood pressure decreased equally in both groups (P < 0.001, at 6 and 12 months versus before treatment). Serum creatinine and estimated glomerular filtration rate changed little during the experimental period in each group. However, urinary protein excretion (P < 0.001), urinary liver-type fatty acid-binding protein (P < 0.001), urinary 8-hydroxy-2'-deoxyguanosine (P < 0.001), blood interleukin-6 (P < 0.001), blood high mobility group box-1 (P < 0.05), and pulse wave velocity (P < 0.01) decreased more in group A than in group B with 12 months of treatment. The percent reductions in intima-media thickness and blood asymmetric dimethylarginine were significantly greater in group A than in group B (P < 0.001).. Benidipine is more effective than amlodipine for protecting renal function and potentially for ameliorating atherosclerosis in hypertensive patients with mild CKD. T-type calcium channel blockers may be effective in patients with CKD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amlodipine; Atherosclerosis; Biomarkers; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Fatty Acid-Binding Proteins; Female; Humans; Inflammation; Kidney Failure, Chronic; Male; Proteinuria

Iron supplementation is a mainstay for management of renal anaemia in patients receiving haemodialysis (HD). Although it is well known that a single intravenous iron (IVIR) administration transiently enhances oxidative stress in HD patients, the consequence of repeated IVIR administration is still unknown. This study aims to clarify the time course of changes in serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, during a period of repeated IVIR administration in HD patients.. Twenty-seven patients (62+/-14 years and 23 males) on long-term HD participated in this study. All patients had been on HD more than 6 months and none had received a blood transfusion or iron therapy in previous 6 months. The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels as a marker of body iron stores: IVIR group (Ht<30% and FTN<100 ng/ml; n=7); High FTN group (Ht>or=30% and FTN>or=100 ng/ml; n=11); and low FTN group (Ht>or=30% and FTN<100 ng/ml; n=9). The IVIR group patients received 40 mg of ferric saccharate i.v. after each HD session until Ht increased by 5%. Serum 8-OHdG and other parameters were prospectively monitored for 10 weeks.. At baseline, the serum ferritin level was independently associated with 8-OHdG in a multiple regression model (total adjusted R2=0.47, P<0.01). All patients in the IVIR group achieved the target Ht level during the study. IVIR administration resulted in significant increases in 8-OHdG levels (0.22+/-0.07-0.50+/-0.16 ng/ml: baseline to 10 week) as compared with both the high FTN group (0.52+/-0.20-0.58+/-0.28 ng/ml) and the low FTN group (0.39+/-0.11-0.36+/-0.11 ng/ml) (ANOVA for repeated measures P<0.01). Additionally, serum 8-OHdG and serum ferritin changed in the same manner.. Repeated IVIR administration for HD patients was associated with signs of increased oxidative DNA injury, as reflected by increased serum levels of 8-OHdG. As these changes were accompanied by increased serum ferritin levels, excess body iron stores might play an important role in oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Anemia, Iron-Deficiency; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Prospective Studies; Recombinant Proteins; Regression Analysis; Renal Dialysis

Hypoxia plays a significant role in the pathogenesis and progression of chronic renal disease. Urinary liver-type fatty acid binding protein (L-FABP) levels reflect the clinical prognosis of chronic renal disease. The calcium channel blocker azelnidipine has anti-oxidative properties and these may contribute to the beneficial effects of this drug. The aim of the present study was to determine whether azelnidipine and/or amlodipine affected urinary protein excretion or the urinary levels of 8-OHdG and L-FABP in hypertensive patients with mild chronic kidney disease (CKD).. Thirty moderately hypertensive chronic kidney disease patients were randomly assigned to 2 treatment groups: azelnidipine 16 mg once daily or amlodipine 5 mg once daily. Treatment was continued for 6 months. Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP were measured before 3 and 6 months after the treatment period.. Both drugs exhibited comparable and significant effects on the systolic and diastolic blood pressure. Azelnidipine decreased heart rate significantly after 3 and 6 months whereas amlodipine increased it significantly after 3 and 6 months. Urinary protein excretion, urinary 8-OHdG and urinary L-FABP levels decreased significantly after 3 months (p < 0.05) and 6 months (p < 0.05) in the azelnidipine group. In contrast, amlodipine showed little effect on urinary protein excretion or the urinary levels of 8-OHdG and L-FABP throughout the experimental period.. Azelnidipine is renoprotective in hypertensive patients with mild CKD and this action is, at least in part, due to the anti-oxidative effect.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Amlodipine; Antioxidants; Azetidinecarboxylic Acid; Blood Pressure; Calcium Channel Blockers; Deoxyguanosine; Dihydropyridines; Fatty Acid-Binding Proteins; Female; Heart Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria

Hemodialyzed patients with chronic kidney disease are prone to atherosclerosis, which occurs due mainly to lipid abnormalities. Abnormal lipid metabolism could result, among others, from increased formation of free radicals and, consequently, oxidative stress in these patients. The objective of the present study was to evaluate the influence of therapy with lovastatin or with a hypolipemic diet only on oxidative stress in hemodialyzed patients. We addressed the issue by measuring the total antioxidant status (TAS) and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG), an oxidative DNA damage metabolite, in the serum. The study group consisted of 71 patients. They were divided into 3 groups: treated with lovastatin (20 mg/day, n=30), with a hypolipemic diet alone (n=28), and untreated controls (n=13). Serum levels of TAS and 8-OHdG (8-hydroxy-2-deoxyguanosine) were determined. Blood samples were collected at the beginning of the study and then after a 6 months' therapy. We found that the level of 8-OHdG decreased considerably only in the lovastatin-treated group; the decrease was from 15.6+/-8.1 to 12.5+/-4.8 ng/ml (P=0.04). In the other two groups changes in 8-OHdG were insignificant. The level of TAS increased significantly in the lovastatin-treated group from 1.28+/-0.20 to 1.37+/-0.116 mmol/l (P=0.011), decreased in the diet-treated group from 1.55+/-0.14 to 1.45+/-0.11 mmol/l (P=0.007), and remained unchanged in the untreated group (1.42+/-0.11 vs. 1.40+/-0.12 mmol/l). We conclude that lovastatin, but not a hypolipemic diet alone, exerts an antioxidant effect in hemodialyzed patients. However, the determinants of the antioxidant effect of statins in patients with chronic renal failure are unclear and their resolution would require alternative study designs.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antioxidants; Deoxyguanosine; Diet, Fat-Restricted; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Lipids; Lovastatin; Male; Middle Aged; Oxidative Stress; Renal Dialysis; Time Factors; Treatment Outcome

Accumulating evidence suggests that oxidative stress is enhanced in patients on regular hemodialysis (HD). Iron supplementation is essential for the treatment of renal anemia, but there is a possibility that it could enhance oxidative stress by inducing the Fenton reaction. Here, we report our investigation of the relation between iron storage and DNA oxidative injury in HD patients.. The study subjects were 48 patients on regular HD (age, 62.7 +/- 12.1 years; HD duration, 67.2 +/- 62.5 months; non-diabetic/diabetic; 22:26). Patients who were positive for hepatitis C virus antibody (HCV Ab), or hepatitis B surface antigen (HBsAg), and those with inflammatory or malignant diseases were excluded. The serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) level, a marker of DNA oxidative injury, was measured before the first HD session of the week in all patients, and factors associated with high serum 8-OHdG were investigated. In 9 patients with a serum ferritin level of more than 1000 ng/ml at study entry, serum 8-OHdG levels were followed up for 6 months in the absence of iron supplementation.. Multivariate analysis showed that the serum ferritin level was a significant and independent determinant of serum 8-OHdG, and serum ferritin correlated significantly with the total dose of iron supplementation during the 6-month period of the study. In the nine patients, without iron supplementation, serum 8-OHdG levels, as well as serum ferritin, decreased significantly during follow-up.. Our results suggest that increased iron storage may induce DNA oxidative injury in patients on regular HD, and that the serum ferritin level is a surrogate marker for this pathological condition.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Anemia; Deoxyguanosine; Female; Ferritins; Follow-Up Studies; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Transferrin

This study focused on the effect of vitamin C on the 8-hydroxy-2'-deoxyguanosine (8-OHdG) level of cellular DNA, as well as 8-oxoguanine-DNA glycosylase 1 (hOGG1) and human MutT homologue (hMTH1) gene expression in peripheral blood lymphocytes of chronic hemodialysis patients.. Sixty chronic hemodialysis patients (35 men and 25 women) were recruited to participate in a randomized, placebo-controlled study. Treatment order is block-randomized with intravenous sodium ascorbate (vitamin C, 300 mg) or placebo (0.9% saline), administered postdialysis three times a week. We evaluated 8-OHdG level, intracellular reactive oxygen species (ROS) production, and gene expression of hOGG1 and hMTH1 in peripheral blood lymphocytes by using high-performance liquid chromatography (HPLC) electrochemical detection method, flow cytometric analysis, and reverse transcription-polymerase chain reaction (RT-PCR), respectively.. A total of 51 patients completed the study (26 in placebo group and 25 in vitamin C group). Mean 8-OHdG levels significantly decreased in total subjects following 8 weeks of vitamin C supplementation (22.9 vs. 18.8/10(6) dG, P < 0.01). The decrease in 8-OHdG levels after vitamin C supplementation was also noted in the patients with ferritin <500 or > or =500 microg/L and transferrin saturation (TSAT) <50 or > or =50% (P < 0.05). But 8-OHdG levels had no significant changes in total patients or in the four subgroups of patients treated with placebo as compared to their baselines. Intracellular ROS production by lymphocytes from the four subgroups of patients, either spontaneous (P < 0.05) or phorbol-12-myristate-13-acetate (PMA)-stimulated (P < 0.001), was significantly reduced after 8 weeks vitamin C supplementation. Steady-state hOGG1 mRNA levels were significantly up-regulated at 24 hours after vitamin C administration (P < 0.05), but hMTH1 mRNA levels were not. The changes in the spontaneous and PMA-stimulated ROS production, and an up-regulation of hOGG1 mRNA expression were not observed in patients treated with placebo as compared to their baselines.. Vitamin C supplementation in chronic hemodialysis patients can reduce the lymphocyte 8-OHdG levels and intracellular ROS production, as well as up-regulate hOGG1 gene expression for repair. There is no compelling evidence for an in vivo pro-oxidant effect of vitamin C on lymphocyte DNA base oxidation, even in the status of increased iron stores.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Antioxidants; Ascorbic Acid; Deoxyguanosine; DNA Glycosylases; DNA Repair Enzymes; Female; Ferritins; Humans; Iron; Kidney Failure, Chronic; Lymphocytes; Male; Middle Aged; Oxidative Stress; Phosphoric Monoester Hydrolases; Reactive Oxygen Species; Renal Dialysis; RNA, Messenger; Transferrin; Up-Regulation

8-Hydroxy 2'-deoxyguanosine (8-OHdG) of leukocyte DNA has been identified as a surrogate marker of oxidative stress in chronic hemodialysis (HD) patients. In this study, we focused on the determinants of the 8-OHdG level in leukocyte DNA of HD patients. We further investigated the influence of vitamin E-modified, regenerated cellulose (CL-E) membrane on the oxidative DNA damage, intracellular reactive oxygen species (ROS) production of granulocytes, and plasma alpha-tocopherol concentration.. 8-OHdG content in cellular DNA of leukocytes was measured by a high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method. Intracellular production of ROS, H2O2 and O2-. were analyzed by flow cytometry in leukocytes with and without phorbol-12-myristate-13-acetate (PMA) stimulation before dialysis, as well as at 15 and 30 minutes of dialysis. Plasma alpha-tocopherol concentration was measured by a HPLC method, and the value of alpha-tocopherol was corrected by total blood lipid concentration.. In the prospective cross sectional study, the mean 8-OHdG level in leukocyte DNA was equally lower in the patients of the CL-E, polymethylmethacrylate (PMMA), and polysulfone (PS) groups as compared with the cellulosic group (ANOVA, P < 0.001). The leukocyte 8-OHdG level correlated negatively with plasma alpha-tocopherol and blood lipid-adjusted plasma alpha-tocopherol, but correlated positively with serum iron and percentage of transferrin saturation. Forward stepwise multiple regression showed that dialysis membrane type, serum iron, and blood lipid-adjusted plasma alpha-tocopherol were the independent determinants of the leukocyte 8-OHdG level in HD patients. Like synthetic membranes, granulocyte ROS production was less augmented during dialysis with the CL-E membrane as compared with the cellulose membrane. Exposure to cellulose membrane impaired intracellular ROS production of granulocytes in response to PMA challenge, whereas the CL-E and synthetic membranes improved the granulocyte responsiveness to PMA. In the longitudinal cross-over study, the 8-OHdG level significantly decreased, and blood lipid-adjusted plasma alpha-tocopherol increased after switching the cellulose membrane to CL-E or synthetic membrane for eight weeks. In contrast, the 8-OHdG level dramatically rose, and blood lipid-adjusted plasma alpha-tocopherol declined after shift of CL-E or synthetic membrane to the cellulose membrane.. CL-E membrane exhibited biocompatible and bioactive characteristics. Like synthetic membranes, treatment with a CL-E dialyzer effectively reduced the 8-OHdG content in leukocyte DNA, suppressed intracellular ROS production of granulocytes, and preserved the plasma level of vitamin E. It could further improve granulocyte responsiveness to a PMA challenge. Reduced DNA damage and improved immune function of leukocytes may reduce the cancer and infection risks in chronic HD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Ascorbic Acid; Biocompatible Materials; Bone Cements; Cellulose; Chromatography, High Pressure Liquid; Cross-Over Studies; Deoxyguanosine; DNA; Female; Flow Cytometry; Humans; Hydrogen Peroxide; Kidney Failure, Chronic; Leukocytes; Male; Membranes, Artificial; Middle Aged; Oxidative Stress; Polymers; Polymethyl Methacrylate; Prospective Studies; Renal Dialysis; Sulfones; Vitamin E

Endothelial dysfunction is common in patients undergoing hemodialysis (HD). However, little is known about the relationship between endothelial dysfunction and coenzyme Q10 (CoQ10) levels in HD patients.. Eligible HD patients were enrolled in this study according to prespecified inclusion and exclusion criteria. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD). Plasma CoQ10, serum malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) levels were measured. The potential confounders identified by univariate analyses (P < 0.15) were selected in a stepwise multiple regression model.. In total, 111 HD patients were enrolled in this study. The mean CoQ10 level was 633.53 ± 168.66 ng/mL, and endothelial dysfunction was prevalent (91.0%) using a cut-off value of 10% FMD. A significant correlation was observed between FMD and plasma CoQ10 level (r = 0.727, P < 0.001). After adjusting for potential parameters, a stepwise multivariate linear regression analysis revealed that CoQ10 level was an independent predictor of FMD (β = 0.018, P < 0.001). When CoQ10 was dichotomized using the median value (639.74 ng/mL), the conclusion remained unchanged (β = 0.584, P < 0.001). Pearson's correlation analyses revealed that plasma CoQ10 level was negatively correlated with MDA (r = -0.48, P < 0.001) and 8-OHdG (r = -0.43, P < 0.001) levels.. Our data demonstrate that impaired brachial artery FMD was common in HD patients. CoQ10 level was independently associated with FMD, and oxidative stress may constitute a link between CoQ10 level and endothelial dysfunction in these patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Brachial Artery; Correlation of Data; Endothelium, Vascular; Female; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Renal Dialysis; Ubiquinone; Vasodilation

It is hypothesized that chronic kidney disease (CKD) induces oxidant stress which contributes to the decline in kidney function. However, few studies have incorporated longitudinal designs and no studies have investigated this association among children. Using data from the Chronic Kidney Disease in Children (CKiD) study, we examined longitudinal associations between urinary biomarkers of oxidant stress, 8-OH deoxyguanosine (8-OHdG) and F2-isoprostane, and measures of renal function and blood pressure among children with CKD. Baseline levels of 8-OHdG were positively associated with estimated glomerular filtration rate (eGFR) over time and a log-unit increase in baseline 8-OHdG predicted a 5.68 ml/min/1.73 m

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Biomarkers; Child; Child, Preschool; Disease Progression; F2-Isoprostanes; Female; Glomerular Filtration Rate; Humans; Infant; Kidney Failure, Chronic; Kidney Function Tests; Longitudinal Studies; Male; Oxidants; Oxidative Stress; Proportional Hazards Models; Prospective Studies

Oxidative stress is involved in the pathogenesis of diabetic kidney disease. We evaluated the association between 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative damage, and end-stage renal disease (ESRD) or death in individuals with type 1 diabetes.. Plasma 8-OHdG concentrations were measured at baseline in participants with type 1 diabetes from GENEDIAB (n = 348) and GENESIS (n = 571) cohorts. A follow-up was conducted in 205 and 499 participants for a mean ± SD duration of 8.9 ± 2.3 years and 5.2 ± 1.9 years, respectively. We tested associations between 8-OHdG concentrations and urinary albumin concentration (UAC) or eGFR at baseline, and the risk of ESRD or all-cause mortality during follow-up. Analyses were performed in pooled cohorts.. The highest UAC (geometric mean [95% CI]) was observed in the third 8-OHdG tertile (tertile 1, 9 [6, 13] mg/l; tertile 2, 10 [7, 16] mg/l; tertile 3, 16 [10, 25] mg/l; p = 0.36 for tertile 1 vs tertile 2 and p = 0.003 for tertile 3 vs tertile 1) after adjustment for potential confounding covariates. The lowest eGFR (mean [95% CI]) was observed in the third tertile (tertile 1, 87 [82, 93] ml min. Higher plasma concentrations of 8-OHdG were independently associated with increased risk of kidney disease in individuals with type 1 diabetes, suggesting that this marker can be used to evaluate the progression of diabetic kidney disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Cross-Sectional Studies; Deoxyguanosine; Diabetes Mellitus, Type 1; DNA Damage; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Oxygen; Prospective Studies; Risk Factors; Sensitivity and Specificity

Renal transplantation (RT), has been considered the best therapeutic option for end stage renal disease (ESRD). Objective. To determine the effect of RT on the evolution of oxidative DNA status. Methods. Prospective cohort (N = 50 receptors of RT); genotoxic damage, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and DNA repair enzyme, human 8-oxoguanine-DNA-N- glycosylase-1 (hOGG1); and antioxidants, superoxide dismutase (SOD) and glutathione peroxidase (GPx), were evaluated. Results. Before RT, 8-OHdG were significantly elevated (11.04 ± 0.90 versus 4.73 ± 0.34 ng/mL) compared to healthy controls (p = 0.001), with normalization after 6 months of 4.78 ± 0.34 ng/mL (p < 0.001). The same phenomenon was observed with hOGG1 enzyme before RT with 2.14 ± 0.36 ng/mL (p = 0.01) and decreased significantly at the end of the study to 1.20 ng/mL (p < 0.001) but was higher than controls, 0.51 ± 0.07 ng/mL (p < 0.03). Antioxidant SOD was elevated at 24.09 ± 1.6 IU/mL versus healthy controls (p = 0.001) before RT; however, 6 months after RT it decreased significantly to 16.9 ± 1.6 IU/mL (p = 0.002), without achieving the levels of healthy controls (p = 0.01). The GPx, before RT, was significantly diminished with 24.09 ± 1.6 IU/mL versus healthy controls (39.0 ± 1.58) (p = 0.01), while, in the final results, levels increased significantly to 30.38 ± 3.16 IU/mL (p = 0.001). Discussion. Patients with ESRD have important oxidative damage before RT. The RT significantly reduces oxidative damage and partially regulates the antioxidant enzymes (SOD and GPx).

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Antioxidants; Deoxyguanosine; DNA Glycosylases; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Oxidative Stress

Subjects with chronic renal failure (CRF) exhibit oxidative genome damage, which may predispose to carcinogenesis, and Gum acacia (GumA) ameliorates this condition in humans and animals. We evaluated here renal DNA damage and urinary excretion of four nucleic acid oxidation adducts namely 8-oxoguanine (8-oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), 8-oxoguanosine (8-oxoGuo) and 8-hydroxy-2-deoxyguanisone (8-OHdg) in rats with adenine (ADE)-induced CRF with and without GumA treatment.. Twenty-four rats were divided into four equal groups and treated for 4 weeks. The first group was given normal food and water (control). The second group was given normal food and GumA (15% w/v) in drinking water. The third group was fed powder diet containing adenine (ADE) (0·75% w/w in feed). The fourth group was fed like in the third group, plus GumA in drinking water (15%, w/v).. ADE feeding induced CRF (as measured by several physiological, biochemical and histological indices) and also caused a significant genetic damage and significant decreases in urinary 8-oxo Gua and 8-oxoGuo, but not in the other nucleic acids. However, concomitant GumA treatment reduced the level of genetic damage in kidney cells as detected by Comet assay and significantly reversed the effect of adenine on urinary 8-oxoGuo.. Treatment with GumA is able to mitigate genetic damage in renal tissues of rats with ADE-induced CRF.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenine; Animals; Comet Assay; Deoxyguanosine; DNA Damage; Guanine; Guanosine; Gum Arabic; Kidney Failure, Chronic; Kidney Function Tests; Male; Random Allocation; Rats, Wistar; Renal Agents

We aimed to evaluate oxidative stress [8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA)] endothelial damage [asymmetric dimethylarginine (ADMA)] and markers of cellular inflammation [interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), neopterin (NP) and high-sensitivity C-reactive protein (hsCRP)] in patients with diabetic nephropathy (DN) and non-diabetic nephropathy who were being administered hemodialysis treatment because of chronic renal failure.. In determining 8-OHdG, IL-6 and TNF-α levels, Enzyme-Linked Immuno-Sorbent Assay method was used. Serum MDA, ADMA and NP levels were determined by using high performance liquid chromatography (HPLC). And hs-CRP values were measured with nephelometric method.. Serum 8-OHdG and MDA levels were found statistically to have increased when compared with those of the control group in patients groups after dialysis. However, serum ADMA and neopterin levels were observed statistically to have decreased when compared with those of the control group in patients groups after dialysis. But, decreases on ADMA and neopterin levels are still much higher than those of control. IL-6 and TNF-α levels were found to have increased when compared with those of control group in patients groups before dialysis.. The oxidative stress in patients with DN, who were being treated with hemodialysis due to chronic renal failure, was higher than that of non-DN patients who were being treated with hemodialysis. In contrast with this, inflammation occurring in non-DN patients was found to have been higher than that of in patients with DN.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Arginine; Biomarkers; C-Reactive Protein; Case-Control Studies; Deoxyguanosine; Diabetic Nephropathies; Female; Humans; Inflammation; Interleukin-6; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Neopterin; Oxidative Stress; Tumor Necrosis Factor-alpha

Accelerated atherosclerosis is the major cause of mortality in patients on chronic haemodialysis (HD). The aim of this study was to evaluate the relationship between oxidative DNA damage [8-hydroxy-2'-deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio)], oxidative stress biomarkers and endothelial function in HD patients as an indicator of atherosclerosis.. Forty-four chronic HD patients without known atherosclerotic disease and 55 age- and sex-matched healthy individuals were included in the study. Plasma malondialdehyde (MDA) levels and 8-OHdG/dG ratio were determined as oxidative stress markers. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as antioxidants. Endothelial function was assessed by ultrasonography.. 8-OHdG/dG ratio and MDA levels were higher in HD patients than controls while SOD and GPx activities were lower in HD patients compared to controls. Flow-mediated dilatation FMD% in HD patients were lower than the control group (7.28 ± 0.79 versus 11.18 ± 0.82, P < 0.001). There was a significant negative correlation between FMD% and 8-OHdG/dG ratio (r = -0.678, P < 0.01) and MDA levels (r = -0.517, P < 0.01), while there was a significant positive correlation between FMD% and SOD (r = 0.538, P < 0.01) and GPx levels (r = 0.720, P < 0.01).. Our data have demonstrated that HD patients exhibit increased oxidative DNA damage and decreased antioxidant activity. We propose that endothelial function is negatively correlated with 8-OHdG/dG ratio and positively correlated with antioxidant enzymes. To our knowledge, this is the first study to demonstrate the inverse relationship between endothelial function and plasma oxidative DNA damage in HD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Atherosclerosis; Biomarkers; Case-Control Studies; Cells, Cultured; Deoxyguanosine; DNA Damage; Endothelium, Vascular; Female; Glutathione; Glutathione Peroxidase; Humans; Kidney Failure, Chronic; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Prognosis; Renal Dialysis; Superoxide Dismutase; Survival Rate

While chronic kidney disease (CKD) is associated with dysmetabolism including a marked insulin resistance, the postprandial response has not comprehensively been studied in CKD patients.. We conducted an intervention study comparing fasting and postprandial circulating biomarkers of glucose and lipid homeostasis, incretins, anabolic hormones, inflammation and oxidative stress in nine prevalent non-diabetic hemodialysis (HD) patients and 10 matched controls assessed after a standardized meal consisting of 75 g of milk fat, 80 g of carbohydrates and 6 g of proteins/m(2) of body surface area.. Glucose and triglyceride increased in a similar manner following the meal, while insulin, C-peptide and glucose-dependent insulinotropic polypeptide increased more in HD patients. HDL and LDL cholesterol decreased slightly with no significant difference between the groups. The elevated baseline growth hormone (GH) in patients dropped, resulting in comparable levels in both groups 240 min after the meal; however, there was no change in insulin-like growth factor 1 (IGF-1) levels. No marked changes of interleukin 6 and tumor necrosis factor-α were observed in either group. An elevation in the DNA oxidative product 8-hydroxydeoxyguanosine was observed in HD patients.. The postprandial state in CKD is characterized by impaired insulin sensitivity with increased incretin levels, along with GH/IGF-1 axis uncoupling and an elevation in an oxidative stress marker.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Blood Glucose; Case-Control Studies; Creatinine; Deoxyguanosine; Dietary Carbohydrates; Dietary Fats; Fasting; Female; Follow-Up Studies; Glomerular Filtration Rate; Growth Hormone; Humans; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Postprandial Period; Prognosis; Triglycerides; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF)-α and oxidative stress are considered to play crucial roles in atherosclerosis and vascular calcification. "Uremic toxins" detected in patients with chronic kidney disease (CKD) could cause impaired signal transduction and dysfunction in many organs. Since phenylacetic acid (PAA), identified as one of the uremic toxins, has an inhibiting property of monocytes as well as osteoblastic cells, we examined the effects of PAA on TNF-α secretion and oxidative stress in vascular endothelial cells. In human aortic endothelial cells, TNF-α secretion was assessed after treatment with PAA using an ELISA kit and following the manufacturer's instructions. For determination of reactive oxygen species (ROS), 8-hydroxydeoxyguanosine (8-OHdG) in the culture medium was measured in the presence or absence of PAA. Treatment with PAA in aortic endothelial cells for 24 h significantly stimulated TNF-α secretion in a dose-dependent manner ranging between 0.5 and 5 mM. On the other hand, the 8-OHdG level in the culture medium was significantly increased in the cells incubated with 1 mM PAA for 12 h. To determine if PAA-induced TNF-α secretion is mediated by ROS production, the effect of free radical scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL) was examined. It was found that PAA-induced TNF-α secretion was significantly inhibited by TEMPOL. Our findings indicate that PAA stimulates TNF-α secretion at least in part through ROS production in aortic endothelial cells. The plasma PAA level was reported to be approximately 3.5 mM in end-stage CKD patients, whereas it was <5 µM in healthy subjects; thus, PAA could be involved in the pathological changes of the vasculature in CKD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aorta; Cells, Cultured; Deoxyguanosine; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Humans; Kidney Failure, Chronic; Oxidative Stress; Phenylacetates; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Increased vascular calcification and oxidative stress are considered as extra renal risk factors at the pathogenesis cardiovascular events in chronic kidney disease (CKD). We investigated matrix Gla protein (MGP) (T-138C, Glu60X, Thr83Ala) and Klotho (Cys370Ser) gene polymorphisms, serum MGP levels, and oxidative stress status of 84 CKD patients and 37 healthy controls. The MGP gene Glu60X and Thr83Ala polymorphisms were significantly associated with CKD. The correlation between T-138C genotype of MGP gene, Cys370Ser genotype of Klotho gene, and CKD was not significant (p > 0.05). At the haplotype analysis, the combination of the X allele of Glu60X and the Thr allele of Thr83Ala showed a significantly increased risk of CKD (p < 0.05). X allele, Thr allele, and C allele of T-138C were associated with diabetes mellitus and CKD phenotypes occurring concurrently (p < 0.01). Serum zinc levels were significantly low in end-stage renal disease (ESRD) patients (p = 0.0001). The total comet score frequency of ESRD patients was higher than that of control group (p < 0.05). The urinary 8-hydroxy-2'-deoxyguanosine levels were significantly high in CKD patients (p < 0.05). According to this study, analyzing the distribution of MGP gene and oxidative stress status would be very informative in order to detect their role at CKD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Deoxyguanosine; Extracellular Matrix Proteins; Female; Genotype; Glucuronidase; Humans; Kidney Failure, Chronic; Klotho Proteins; Male; Matrix Gla Protein; Middle Aged; Oxidative Stress; Polymerase Chain Reaction; Polymorphism, Genetic; Prognosis; Reference Values; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index; Statistics, Nonparametric; Young Adult

It has been proposed that reactive oxygen species play a role in renal fibrosis. 8-OHdG, a metabolite of oxidative damage to leukocyte DNA, has been identified as a marker of oxidative stress in patients with chronic renal failure.. Seventy-four patients following nephrectomy were retrospectively enrolled. Immunohistochemical analysis of the renal expression of 8-OHdG in the nephrectomised kidneys was performed and associations between renal expression of 8-OHdG and renal fibrosis were evaluated.. Patients with higher interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), increased percentage of chronic kidney disease (CKD) and urothelial cell carcinoma. The renal tissues with higher IFS had lower expressions of 8-OHdG in normal tubular cytoplasm (NTc) (35.7% vs. 64.3%, p = 0.011) and normal tubular nuclei (NTn) (28.6% vs. 71.4%, p = 0.023). Univariate analysis showed that IFS and GFS correlated with the NTc 8-OHdG expression and IFS negatively correlated with NTn 8-OHdG expression. Multivariate stepwise regression revealed that serum creatinine (r = 0.351 for IFS, p = 0.021; r = 0.563 for GFS, p < 0.001) and intensity of 8-OHdG expression in NTc (r = 0.397 for IFS, p = 0.01; r = 0.278 for GFS, p = 0.043) were the independent factors predicting IFS or GFS.. This study demonstrated that the intensity of 8-OHdG expression in NTc was associated with the severity of renal fibrosis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Cytosol; Deoxyguanosine; Female; Fibrosis; Humans; Immunohistochemistry; Kidney Failure, Chronic; Kidney Tubules; Male; Middle Aged; Severity of Illness Index

The aim of this study was to evaluate the oxidative DNA damage, antioxidant activity, and effects of antihypertensive drugs on oxidative stress in hypertensive patients with different stages of chronic kidney disease (CKD). Fifty-three non-dialyzed hypertensive CKD patients were included by the study. Serum and urinary 8-hydroxydeoxy guanosine (8-OHdG) levels (as a marker of oxidative DNA damage), serum superoxide dismutase (SOD), and glutathione peroxidase (G-Px) activities (as antioxidant enzymes) were measured. SOD activity was higher and G-Px activity was lower in the patient group as compared to control group. Serum and urinary 8-OHdG levels were found to be higher in the patients with proteinuria greater than 3 g/day than those in the patients with proteinuria less than 3 g/day. It has been determined that G-Px activity and urinary 8-OHdG level were lower in the patients treated with angiotensin-converting enzyme (ACE) inhibitor compared to patients treated with calcium channel blocker. The present data show oxidative DNA damage at a higher level in the patients with proteinuria greater than 3 g/day. In comparison to a calcium channel blocker, an ACE inhibitor seems much more protective against oxidative DNA damage in hypertensive patients with different stages of CKD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Deoxyguanosine; DNA Damage; Female; Glutathione Peroxidase; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Superoxide Dismutase; Young Adult

A sensitive and specific assay aimed at measuring the oxidized nucleic acids, 8-oxoguanine (8-oxoGua), fapy-guanine (Fapy-Gua), 8-oxoguanosine (8-oxoGuo), 8-oxo-2'-deoxyguanosine (8-oxodG) has been developed by coupling reversed phase liquid chromatography (HPLC) with electrospray tandem mass spectrometry detection (MS/MS) and isotope dilution. The HPLC-MS/MS approach with multiple reaction monitoring (MRM) allowed for the sensitive determination of 8-oxoGua, Fapy-Gua, 8-oxoGuo, and 8-oxodG in human urine samples. There is no sample preparation needed except for the addition of buffer and (13)C- and (15)N-labeled internal standards to the urine prior to sample injection into the HPLC-MS/MS system. This method was tested in urine samples from non-smokers, smokers, non-smokers with chronic kidney disease (CKD) and smokers with CKD, to assess the level of oxidative damage to nucleic acids. Markers of both RNA and DNA damage were significantly increased in the smokers with and without CKD compared to their respective control subjects. These findings suggest that a highly specific and sensitive analytical method such as isotope dilution HPLC-MS/MS may represent a valuable tool for the measurement of oxidative stress in human subjects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Carbon Isotopes; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA Damage; Guanine; Guanosine; Humans; Indicator Dilution Techniques; Kidney Failure, Chronic; Molecular Structure; Nitrogen Isotopes; Oxidation-Reduction; Oxidative Stress; Pyrimidines; Reference Standards; Smoking; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

The pathogenesis of diabetic nephropathy remains far from clear, partly due to the lack of a suitable animal model that mimics human renal disease in type 2 diabetes. In this study, the natural history of renal manifestations in ZSF1 rats, a recently developed rodent model of type 2 diabetes, is described. Male ZSF1 rats developed obesity and hyperglycemia by 20 weeks of age on a high-carbohydrate diet. They also developed systolic and diastolic hypertension, hypercholesterolemia, profound hypertriglyceridemia, proteinuria, and renal failure. Renal histology demonstrated changes consistent with early diabetic nephropathy, including arteriolar thickening, tubular dilation and atrophy, glomerular basement membrane thickening, and mesangial expansion. Furthermore, renal nitric oxide production was decreased, and homogenates from renal cortices demonstrated reduced expression of renal endothelial and inducible nitric oxide synthases. These changes were associated with increased urinary levels and renal expression of 8-hydroxydeoxyguanosine, an indicator of mitochondrial oxidative stress, as well as with increased renal peroxynitrite formation. Administration of either insulin or the antioxidant alpha-lipoic acid decreased proteinuria and oxidative stress, but only the former slowed progression of renal failure. We conclude that ZSF1 rats represent the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Animals, Genetically Modified; Deoxyguanosine; Diabetic Nephropathies; Disease Models, Animal; Female; Glomerular Filtration Rate; Glomerular Mesangium; Kidney Failure, Chronic; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats; Rats, Inbred Strains

Oxidative stress is at play in the progression of chronic renal failure (CRF) and in the genesis of atherosclerosis. The aim of the present study was to evaluate the factors that might influence the oxidative-antioxidative balance in patients on hemodialysis. The study group consisted of 71 hemodialysis patients due to CRF. Sixteen healthy subjects constituted a control group. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), C-reactive protein (CRP), and the blood lipid profile were measured in both groups. The results showed significantly higher mean levels of both 8-OHdG and CRP in the hemodialysis patients compared with that in the control subjects. The highest level of 8-OHdG was found in the subgroups of the patients with CRF primarily caused by diabetes (16.4 ng/ml) and with hypertensive nephropathy (15.8 ng/ml). More than a 2.5-fold higher level of 8-OHdG in the hemodialysis patients compared with the control subjects points to the presence of intensive oxidative stress in the patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; C-Reactive Protein; Deoxyguanosine; Diabetes Complications; Glomerulonephritis; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Nephritis, Interstitial; Oxidative Stress; Renal Dialysis

8-Hydroxy-2'-deoxyguanosine (8-OHdG), a product of oxidized DNA, is increased in haemodialysis (HD) patients, but the clinical relevance of enhanced 8-OHdG production in these patients remains unknown.. We cross-sectionally measured serum 8-OHdG in 73 patients on maintenance HD (age 68+/-2 years, time on HD 85+/-11 months, male/female=42/31), and examined the relationship between blood 8-OHdG and the severity of renal anaemia and the weekly dosage of recombinant human erythropoietin (rHuEPO).. There was a significant increase in serum 8-OHdG in HD patients compared with normal subjects. Serum 8-OHdG was positively correlated with the patients' age (r=0.231, P<0.05) but not with the duration of HD. Serum 8-OHdG was significantly higher in diabetic subjects than in non-diabetic subjects (P<0.05). Serum 8-OHdG had a significant inverse correlation with haemoglobin (Hb) (r=-0.526, P<0.01) but a positive correlation with the rHuEPO dose (r=0.443, P<0.01) and the ratio of the weekly rHuEPO dose divided by Hb (r=0.487, P<0.01). Serum 8-OHdG was not correlated with inflammatory and nutritional parameters.. These findings suggest that the elevation of circulating 8-OHdG may be associated, at least in part, with rHuEPO resistance in HD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Anemia; Cross-Sectional Studies; Deoxyguanosine; Drug Resistance; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Recombinant Proteins; Renal Dialysis

The aim of this study was to determine the significance of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is known as a marker of oxidative stress in vivo, in patients with chronic renal failure (CRF). Fifty-one non-dialysed CRF patients (29 men and 22 women; mean +/- SD age, 57.8 +/- 12.8 years) who were under dietary therapy for at least 6 months were enrolled in the study. Both serum and urinary 8-OHdG levels were measured by using high-sensitive enzyme-linked immunosorbent assay (ELISA) kits. We examined the relationship between 8-OHdG levels and clinical indices in patients with CRF. As a result, the serum 8-OHdG level was strongly correlated with serum levels of urea nitrogen (UN; r = 0.58; P < 0.0001), creatinine (Cr; r = 0.53; P < 0.0001), and beta2-microglobulin (beta2-MG; r = 0.54; P < 0.0001). Furthermore, the serum 8-OHdG level was inversely correlated with creatinine clearance (Ccr; r = -0.54; P < 0.0001). In contrast, urinary 8-OHdG level was not correlated with any of the clinical parameters. This is the first report of 8-OHdG level determination in patients with CRF. It is suggested that serum 8-OHdG level is not sufficient as a marker of oxidative damage in patients with CRF, and it should be corrected according to the residual renal function to estimate the accurate degree of oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged

This study focuses on the extent of oxidative DNA damage in peripheral blood leukocytes of chronic peritoneal dialysis (CPD) patients. 8-Hydroxy 2'-deoxyguanosine (8-OHdG) contents in peripheral leukocyte DNA were measured by an HPLC-electrochemical detection method in 24 age- and sex-matched healthy subjects, 22 nondialyzed patients with advanced renal failure, and 42 CPD patients. Mean 8-OHdG content was the highest in CPD patients, followed by the nondialyzed patients, and then by the healthy subjects (19.4 versus 11.9 versus 8.3/10(6) dG; ANOVA P < 0.001). In nondialyzed subjects, peripheral leukocyte 8-OHdG contents inversely correlated with renal creatinine clearance (r = -0.772; P < 0.001). Deficiency of blood antioxidants in CPD and nondialyzed patients was expressed by the lower plasma levels of ascorbate, cholesterol-standardized alpha-tocopherol and whole-blood reduced glutathione, and the higher levels of whole-blood oxidized glutathione as compared with healthy subjects (ANOVA P < 0.05). Mean serum ferritin and iron levels and transferrin saturation were higher in the CPD patients than those in the nondialyzed patients and controls (ANOVA P < 0.05). Flow cytometric analyses of intracellular reactive oxygen species production of peripheral leukocytes showed that spontaneous production by granulocytes, as well as phorbol-12-myristate-13-acetate (PMA)-induced production by granulocytes, lymphocytes and monocytes, were the highest from CPD patients, followed by nondialyzed patients, and then by the healthy subjects (ANOVA P < 0.05). Forward stepwise multiple regression disclosed that uremia, PD treatment, spontaneous and PMA-induced reactive oxygen species production in leukocytes, and serum iron were the independent determinants of peripheral leukocyte 8-OHdG content (R(2) = 0.769; P < 0.001). In conclusion, profound increased 8-OHdG levels in peripheral leukocyte DNA occur in the course of chronic renal failure, gradually increase with its progression, and are further exacerbated by PD treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Analysis of Variance; Antioxidants; Biomarkers; Chi-Square Distribution; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Deoxyguanosine; DNA Damage; Female; Flow Cytometry; Humans; Kidney Failure, Chronic; Leukocytes; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Peritoneal Dialysis; Prospective Studies

Oxidative stress during hemodialysis is thought to promote the progression of vascular complications in hemodialysis patients. The protective role of vitamin E as a lipophilic antioxidant against oxidative stress has been widely investigated. Here we investigated the effects of a vitamin E-coated regenerated cellulose hollow fiber dialyzer (CL-EE) on oxidative stress compared with a polysulfone hollow fiber (CL-PS).. For at least three months before beginning the protocol, 10 nondiabetic (NDM) patients (70.0 +/- 7.5 years; 6 males and 4 females) and 8 diabetic (DM) patients (65.0 +/- 7.4 years; 4 males, 4 females) were dialyzed with CL-PS. After that, we treated all of the patients with CL-EE for six months. Malondialdehyde (MDA), advanced glycation end products (AGEs), and 8-hydroxydeoxyguanosine (8-OHdG) were monitored as biomarkers for oxidative stress at the start and then at one, three, and six months into treatment with CL-EE.. Serum MDA, AGE, and 8-OHdG levels increased after the hemodialysis with CL-PS. The increase of the biomarkers was completely prevented by a single use of CL-EE. Long-term hemodialysis with CL-EE for six months significantly reduced the basal levels of the oxidant markers at one month for AGE and at six months for 8-OHdG in both DM and NDM patients. Serum MDA was reduced in only DM patients at three months. The improvement of the oxidative stress with CL-EE was more prominent in the DM patients.. Long-term treatment with CL-EE efficiently improves the oxidative stress associated with hemodialysis and potentially reduces dialysis complications due to oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Antioxidants; Cellulose; Deoxyguanosine; Diabetic Nephropathies; Female; Free Radical Scavengers; Glycation End Products, Advanced; Humans; Kidney Failure, Chronic; Kidneys, Artificial; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Polymers; Renal Dialysis; Sulfones; Time Factors; Vitamin E

It has been reported that advanced glycosylation end products (AGEs) play an important role in the development of diabetic complications. To evaluate the relationship between serum AGEs and diabetic nephropathy, we measured serum AGE levels in diabetic patients with normoalbuminuria (N), microalbuminuria (M), overt proteinuria (O), and hemodialysis (HD), non diabetic patients with nephropathy, and age-matched control subjects using the enzyme-linked immunosorbent assay (ELISA). Urine AGE levels were also measured in these subjects except group HD. Serum AGE levels in diabetic patients were not significantly higher than those in the normal subjects. When we compared serum AGE levels among various stages of diabetic nephropathy, groups O and HD had significantly higher serum AGE levels than the other groups. Serum AGE levels in group HD were almost 6-fold higher than those in groups N and M. In contrast, there were no significant differences in urinary AGE levels among any diabetic groups. As for the variables that determine serum AGE levels in diabetic patients, there was no significant correlation between serum AGEs and fasting blood glucose, hemoglobin A1c (HbA1c), or duration of diabetes. In contrast, serum AGEs showed a strong correlation with serum creatinine and an inverse correlation with creatinine clearance. To evaluate the relationship between serum AGEs and oxidative stress in diabetic nephropathy, urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde (MDA), which are biological markers of total oxidative stress in vivo, were also examined. Both urinary 8-OHdG and serum MDA levels were significantly higher in diabetic patients with proteinuria versus those without proteinuria. However, there was no significant correlation between serum AGEs and urinary 8-OHdG or serum MDA levels in diabetic patients. These results suggest that the accumulation of serum AGEs in diabetic nephropathy may be mainly due to decreased removal in the kidney rather than increased production by high glucose levels or oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Albuminuria; Deoxyguanosine; Diabetes Mellitus; Diabetic Nephropathies; Female; Glycation End Products, Advanced; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Proteinuria; Renal Dialysis

In contrast to proteins and lipids, oxidative damage to DNA has not been well studied in patients undergoing hemodialysis (HD). We hypothesized that phagocytes are activated after blood-membrane contact during HD, and oxidants from metabolic activation can damage leukocyte DNA. To test this hypothesis, the 8-hydroxy-2'-deoxyguanosine (8-OHdG) content of leukocyte DNA was measured by high-performance liquid chromatography electrochemical detection method in 35 age- and sex-matched healthy subjects, 22 undialyzed patients with advanced renal failure, and 109 HD patients to assess the relation between oxidative DNA damage and complement-activating membranes, blood antioxidants, and iron status. Dialysis membranes were classified into complement-activating (cellulose; n = 55) and non-complement-activating (polymethylmethacrylate [PMMA]; n = 35; polysulfone [PS]; n = 19) membranes. We found increased oxidative stress in undialyzed and HD patients based on a decrease in plasma levels of ascorbate and alpha-tocopherol adjusted for blood lipid (alpha-tocopherol/lipid), serum albumin, and reduced glutathione levels in whole blood and an increase in oxidized glutathione levels in whole blood compared with controls (P < 0.001). The greatest 8-OHdG level in leukocyte DNA was in HD patients, followed by undialyzed patients and healthy controls (P < 0.001), and was significantly greater in HD patients using cellulose membranes than those using PMMA or PS membranes (P < 0.001). 8-OHdG levels correlated with plasma alpha-tocopherol/lipid (r = -0.314; P < 0.005), serum iron (r = 0. 446; P < 0.001), and transferrin saturation values (r = 0.202; P < 0.05) in the analysis of all HD patients. In a 6-week crossover study, 8-OHdG levels significantly decreased after the switch from cellulose to synthetic membranes for 2 weeks and increased after the shift from synthetic to cellulose membranes (P < 0.05). Iron metabolism indices and plasma alpha-tocopherol/lipid values did not change significantly in the study period. We conclude that 8-OHdG content in leukocyte DNA is a biomarker of oxidant-induced DNA damage in HD patients. Oxidative DNA damage is a consequence of uremia, further augmented by complement-activating membranes.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Case-Control Studies; Complement Activation; Cross-Over Studies; Deoxyguanosine; DNA; DNA Damage; Female; Glutathione; Humans; Kidney Failure, Chronic; Leukocytes; Male; Membranes, Artificial; Middle Aged; Oxidation-Reduction; Oxidative Stress; Renal Dialysis

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenine; Animals; Deoxyguanosine; DNA Damage; Free Radicals; Kidney; Kidney Failure, Chronic; Male; Oxygen; Rats; Rats, Inbred Strains