Urinary 8-OHdG Levels Research Articles

Response: Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2′-deoxyguanosine and biopyrrin in atrial fibrillation: Effect of sinus rhythm restoration

Herein we are responding to the comments of Dr. Ulas et al [ [1] Ulas T. Hacibekiroglu T. Sezen H. Buyukhatipoglu H. Comment on: Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2'-deoxyguanosine and biopyrrin in atrial fibrillation: Effect of sinus rhythm restoration. Int J Cardiol. 2013; 167: 1643 Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar ]. Firstly, they are concerned whether the urinary 8-OHdG levels reflect the actual oxidative stress levels in tissue. We agree that urinary 8-OHdG could be secondary to atrial oxidative damage because, as have been previously reported, urinary 8-OHdG levels are regarded as putative biomarkers of systemic oxidative damage [ [2] Shigenaga M.K. Gimeno C.J. Ames B.N. Urinary 8-hydroxy-2′-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A. 1989; 86: 9697-9701 Crossref PubMed Scopus (694) Google Scholar ]. Although this is a critical limitation in human clinical studies, a lot of in vivo studies have reported a significant association between urinary 8-OHdG levels and oxidative stress levels in tissue; moreover, our colleagues have reported a significant correlation between oxidative stress and ischemic heart diseases—this was proved by measuring urinary 8-OHdG levels [ 3 Nagayoshi Y. Kawano H. Hokamaki J. et al. Urinary 8-hydroxy-2′-deoxyguanosine levels increase after reperfusion in acute myocardial infarction and may predict subsequent cardiac events. Am J Cardiol. 2005; 95: 514-517 Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar , 4 Hokamaki J. Kawano H. Yoshimura M. et al. Urinary biopyrrins levels are elevated in relation to severity of heart failure. J Am Coll Cardiol. 2004; 43: 1880-1885 Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar ]. We therefore believe that the measurement of urinary 8-OHdG is adequate to justify our conclusions. We also could have evaluated the anti-oxidant markers, such as plasma EC-SOD, as they suggested [ [5] Ulas T. Tursun I. Demir M.E. Dal M.S. Buyukhatipoglu H. Comment on: Infusion of lin-/sca-1+ and endothelial progenitor cells improves proinflammatory and oxidative stress markers in atherosclerotic mice. Int J Cardiol. 2013; 164: 128 Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar ]. At this point in time, it is not possible, nor reasonable, to investigate these anti-oxidant markers because there are insufficient samples available.

Prevalence of Post-Traumatic Stress Disorder after the Great East Japan Earthquake in Patients with Cardiovascular Diseases -The CHART-2 Study-

Possible role of brain natriuretic peptide (BNP) as a biomarker for risk stratification in the general population has received attention. However, determinants of plasma BNP level in apparently healthy subjects remains unclear. Here we addressed this issue by analysis of data in the Tanno-Sobetsu Study. Of 638 study participants in 2008, 369 subjects were randomly selected for determination of plasma BNP and adiponectin and urine 8-hydrodeoxyguanosine (8-OHdG). We excluded subjects on medication and data from 199 subjects (60.9613.1 y/o, 45% male) were used for the analysis. Plasma BNP level was 18.9619.2(SD) pg/ml. In univariate analysis, plasma BNP was significantly correlated with age (r 5 0.37), body mass index (BMI), systolic (r 5 0.28) and diastolic (r 5 0.20) blood pressure, adiponectin (r 5 0.42), urine albumin-to-creatine (Cr) ratio (r 5 0.20), urine sodium-to-Cr ratio and V1S+V5R voltage. In stepwise multiple logistic analysis, age, BMI, diastolic pressure, plasma adiponectin, urine albuminto-Cr ratio and urine 8-OHdG-to-Cr ratio were shown to be independent predictors of BNP level, and the model explained 31% variation of plasma BNP. Plasma adiponectin and urine 8-OHdG levels were positive and negative predictors, respectively, suggesting that their responses are secondary to change in plasma BNP. The present results indicate that age, blood pressure and renal factor reflected by urine albumin are primary determinants of plasma BNP level in apparently healthy subjects.

Urinary 8-hydroxy-2′-deoxyguanosine as a Novel Marker for Predicting the Inflammatory Activity in Patients with Cardiac Sarcoidosis

(8-OHdG), a marker of oxidative stress, was related to LV remodeling in dilated cardiomyopathy (DCM). Methods: We performed full study of cardiac catheterization including endomyocardial biopsy from LV in 35 patients with DCM (left ventricular ejection fraction (LVEF)52865%). Biopsy samples were stained with sirius red to evaluate myocardial fibrosis, and also stained with immunohistochemical method using anti-8-OHdG antibody to evaluate myocardial oxidative stress. In 150 DCM patients, moreover, we examined whether urinary 8-OHdG levels correlated with LVEF, LV end-diastolic volume index (LVEDVI) and LV mass index (LVMI), peak early diastolic mitral annulus velocity (e’)by echocardiography. Results: Biopsy samples data showed that the ratio of oxidized nuclei in cardiomyocytes and CVF were significantly increased in patients with DCM as compared with normal subjects. A direct correlation was found between the positive staining ratio of nuclei and CVF (n535, r50.64, P!0.001). Urinary 8-OHdG was also significantly higher in DCM patients than in control subjects (DCM; n5150: 13.5 63.1 ng/ml vs control; n530: 8.061.9 ng/ml, P!0.001). There was a significant correlation between urinary 8-OHdG and LVEF, or LVEDVI, e’. Conclusions: These findings suggest that urinary 8-OHdG may be a clinically-useful marker for LV remodeling associated with DCM.

Acute Hypertensive Heart Failure Patients Show Paradoxical Hemoconcentration on Admission

(8-OHdG), a marker of oxidative stress, was related to LV remodeling in dilated cardiomyopathy (DCM). Methods: We performed full study of cardiac catheterization including endomyocardial biopsy from LV in 35 patients with DCM (left ventricular ejection fraction (LVEF)52865%). Biopsy samples were stained with sirius red to evaluate myocardial fibrosis, and also stained with immunohistochemical method using anti-8-OHdG antibody to evaluate myocardial oxidative stress. In 150 DCM patients, moreover, we examined whether urinary 8-OHdG levels correlated with LVEF, LV end-diastolic volume index (LVEDVI) and LV mass index (LVMI), peak early diastolic mitral annulus velocity (e’)by echocardiography. Results: Biopsy samples data showed that the ratio of oxidized nuclei in cardiomyocytes and CVF were significantly increased in patients with DCM as compared with normal subjects. A direct correlation was found between the positive staining ratio of nuclei and CVF (n535, r50.64, P!0.001). Urinary 8-OHdG was also significantly higher in DCM patients than in control subjects (DCM; n5150: 13.5 63.1 ng/ml vs control; n530: 8.061.9 ng/ml, P!0.001). There was a significant correlation between urinary 8-OHdG and LVEF, or LVEDVI, e’. Conclusions: These findings suggest that urinary 8-OHdG may be a clinically-useful marker for LV remodeling associated with DCM.

Association between Oxidative Stress Assessed by Urinary 8-Hydroxydeoxyguanosine and the Cardiac Function in Hypertensive Patients without Overt Heart Disease

Although increased oxidative stress is known to be associated with worsened cardiac function in chronic heart failure, consensus is still lacking regarding the association between oxidative stress and cardiac function in hypertensive patients without overt heart disease. This study aimed to evaluate the association between oxidative stress assessed by urinary 8-hydroxydeoxyguanosine (8-OHdG) and cardiac function in hypertensive patients without overt heart disease. We enrolled a total of 80 hypertensive patients (70 ± 11 y) who had been taking antihypertensive medications for at least 1 year. Urinary 8-OHdG levels were measured by an immunochromatographic assay (ICR-001, Selista Inc., Tokyo, Japan). Echocardiography was performed to assess the left ventricular (LV) diastolic function by measuring early diastolic mitral annular velocity (e′) and the ratio of early transmitral flow velocity (E) to e′ (E/e′). Urinary 8-OHdG was correlated with E/e′ (r = 0.346, P = .002), e′ (r = −0.310, P = .005), and HbA1c (r = 0.276, P = .013). Multiple linear regression analysis revealed that only e′ (β = −0.343, P = .004) was an independent determinant of urinary 8-OHdG. In conclusion, decreased e′ is independently associated with elevated urinary 8-OHdG, a marker of oxidative stress, in hypertensive patients. Therefore, an elevated urinary 8-OHdG level may be useful in detecting subclinical LV diastolic dysfunction in hypertensive patients without overt heart disease.

Cross‐sectional and longitudinal analysis of an oxidative stress biomarker for spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. The aim of this study was to verify whether urinary 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, is a biomarker for SBMA. We measured the levels of urinary 8-OHdG in 33 genetically confirmed SBMA patients and 32 age-matched controls over a 24-month period at 6-month intervals. Urinary 8-OHdG levels in SBMA patients were significantly elevated compared with those of controls and correlated well with motor function scores. During the follow-up period, urinary 8-OHdG levels increased and correlated with motor function at each time-point. In addition, urinary 8-OHdG levels at baseline were correlated with changes in the 6-minute walk test during 24 months. Urinary 8-OHdG is a biomarker for SBMA, reflecting the severity and possibly predicting the deterioration of motor function.

Comparison of 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels using mass spectrometer and urine albumin creatinine ratio as a predictor of development of diabetic nephropathy

Background. Measurement of urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) has recently become more popular as a means of assessing oxidative stress in the human body. The aim of this study is to compare the levels of urine 8-OHdG in patients with type 2 diabetes with and without nephropathy and to evaluate its role as a biochemical marker for distinguishing these patients from healthy and patients without complications. Methods. For this purpose, 52 patients with type 2 diabetes mellitus (32 with nephropathy (DMN), 20 without nephropathy (DM)) and 20 healthy control subjects (C) were included in this study. The urine concentrations of 8-OHdG were measured by modified LC-MS/MS method and compared with the first morning voiding urine albumin/creatinine ratio (UACR) and HbA1c values of the same patients. Results. The concentrations of urine 8-OHdG in DMN and DM patients were higher than those of the control subjects (3.47 ± 0.94, 2.92 ± 1.73, 2.1 ± 0.93 nmol/mol creatinine, respectively). But there was no statistical difference between DMN and DM (p = 0.115). There is significant correlation between urinary 8-OHdG and UACR (r = 0.501, p < 0.001). According to ROC analysis, the AUC value of HbA1c was higher than the value of the AUC of 8-OHdG (0.882 and 0.771, respectively). Conclusions. This study shows that the urine 8-OHdG levels increase in diabetic patients. However, urinary 8-OHdG is not a useful clinical marker, compared with UACR, to predict the development of diabetic nephropathy in diabetic patients.

Effect of mercury (Hg) dental amalgam fillings on renal and oxidative stress biomarkers in children

We examined the effect of mercury (Hg) associated with dental amalgam fillings on biomarkers of renal and oxidative stress in children between the ages of 5–15.5years. Urine samples were analyzed for N-acetyl-β-d-glucosaminidase (NAG), α1-microglobulin (α1-MG), β2-microglobulin (β2-MG), retinol binding protein (RBP), albumin (ALB), 8-hydroxy-2-deoxyguanosine (8-OHdG) and malondialdehyde (MDA). The level of urinary Hg (UHg-C) was calculated as μg/g creatinine. Multiple regression analyses revealed that the excretion of urinary NAG was significantly associated with the presence of dental amalgam fillings (β=0.149, P=0.03) and the levels of UHg-C (β=0.531, P=0), with an interaction between the two (P=0). The increase in urinary NAG in relation to UHg-C levels had a dose–effect pattern. The lowest observed effect was seen at UHg-C levels above 1.452μg/g creatinine, which is lower than previously reported. In contrast, α1-MG was negatively associated with the presence of dental amalgam fillings (β=−0.270, P=0), but positively with UHg-C levels (β=0.393, P=0). There were 7 children without, and one child with, dental amalgam fillings with urinary α1-MG levels above the reference limit of >7mg/g creatinine. Even though α1-MG seems to be a reliable biomarker for early changes in renal functions, it might exert its effect only at a higher level of exposure. An inverse relationship was also observed between urinary 8-OHdG levels and the presence of dental amalgam fillings. This might suggest that the dental amalgam does not increase DNA damage but reduces the capacity to repair DNA, leading to lower urinary excretion of 8-OHdG. On the other hand, we found that Hg affected the excretion of urinary 8-OHdG in a dose-related pattern that was mostly associated with long-term exposure to low Hg levels. Urinary NAG levels were positively associated with urinary MDA levels (β=0.516, P=0) but not with 8-OHdG (β=0.134, P=0.078) after adjustment for potential confounders. Both UHg-C and the presence of dental amalgam fillings remained predictors of the NAG model. Our data provide evidence that low exposure to Hg from dental amalgam fillings exerts an effect on kidney tubular functions in children. Oxidative stress may have played a role in this mechanism. The results of this study would also suggest that urinary NAG is the most sensitive of all the investigated renal biomarkers. These results should be confirmed with further investigation.

The Relation of Urinary 8-OHdG, A Marker of Oxidative Stress to DNA, and Clinical Outcomes for Ischemic Stroke

Background:Oxidative stress/free radical generation after ischemic stroke contributes to neuronal cell injury. We evaluated the utility of an oxidative stress marker, urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), to demonstrate an association between the changes of 8-OHdG and outcomes after acute ischemic stroke. Methods:We enrolled 44 patients (26 males and 18 females) who visited our hospital due to acute ischemic stroke. Urine was collected on admission and on Days 7, and 8-OHdG was measured by ELISA. The relationships between 8-OHdG levels, stroke subtypes, and clinical outcomes based on the NIHSS and modified Rankin Scale (mRS) upon discharge was evaluated. Results:In the overall cohort, the mean urinary level of 8-OHdG on Day 7 was increased than that on Day 0. The 8-OHdG levels on Day 0 were not different between patients with poor and good outcomes. However, an increasing rate from Day 0 to 7 (Δ 8-OHdG) in stroke patients with a poor outcome(mRS ≥3) was significantly higher than those with a good outcome (mRS ≤2) (2.54 vs 39.44, p = 0.004). Conclusions:The biochemical changes related to 8-OHdG and oxidative stress may be considered a marker of ischemic brain injury and clinical outcome of ischemic stroke.

Urinary total arsenic and 8-hydroxydeoxyguanosine are associated with renal cell carcinoma in an area without obvious arsenic exposure

8-Hydroxydeoxyguanosine (8-OHdG) is one of the most reliable and abundant markers of DNA damage. The study was designed to explore the relationship between urinary 8-OHdG and renal cell carcinoma (RCC) and to investigate whether individuals with a high level of 8-OHdG would have a modified odds ratio (OR) of arsenic-related RCC. This case–control study was conducted with 132 RCC patients and 245 age- and sex-matched controls from a hospital-based pool between November 2006 and May 2009. Pathological verification of RCC was completed by image-guided biopsy or surgical resection of renal tumors. Urinary 8-OHdG levels were determined using liquid chromatography with tandem mass spectrometry (LC–MS/MS). Concentrations of urinary arsenic species, including inorganic arsenic, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were determined by a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Level of urinary 8-OHdG was significantly associated with the OR of RCC in a dose–response relationship after multivariate adjustment. Urinary 8-OHdG was significantly related to urinary total arsenic. The greatest OR (3.50) was seen in the individuals with high urinary 8-OHdG and high urinary total arsenic. A trend test indicated that the OR of RCC was increased with one of these factors and was further increased with both (p=0.002). In conclusion, higher urinary 8-OHdG was a strong predictor of the RCC. High levels of 8-OHdG combined with urinary total arsenic might be indicative of arsenic-induced RCC.

Association of urinary 8-OHdG with lifestyle and body composition in elderly natural disaster victims living in emergency temporary housing

Residents who lost land and houses due to disasterous heavy rainfall-related events on July 13, 2004 and the Chuetsu Earthquake on October 23, 2004 were moved to emergency temporary housing. The change in life style due to living under such conditions is assumed to increase oxidative stress level. In this study, we investigated the oxidative stress level in elderly residents of emergency temporary housing, and analyzed its association with lifestyle and body composition following these disasters. A noninvasive oxidative stress marker, urinary 8-hydroxydeoxyguanosine (8-OHdG), and body composition were measured in 73 elderly residents of emergency temporary housing. In the elderly female residents, the urinary 8-OHdG level tended to decrease with time after the disasters. 8-OHdG levels were slightly higher in females than males and significantly higher among those who exercised regularly compared to those who did not, particularly in females. A weak correlation was noted between the urinary 8-OHdG level and muscle ratio in females. The in vivo oxidative stress level in our study cohort of elderly residents of emergency temporary housing changed following the change in life style, but remained within the normal range. The increase in oxidative stress levels of elderly females was related to menopause. A decrease in estrogen levels due to menopause inhibits its antioxidant effects, which increases 8-OHdG levels. Although it is difficult to determine, a decrease in daily stressors over time following the disaster could be a cause of the decrease in oxidative stress levels. We suggest that the close evaluation of the stress level of disaster victims is desirable, in combination with evidence of antioxidative substances and the psychosocial influence of suffering as a consequence of the disaster.

Traffic-Related Air Pollution and DNA Damage: A Longitudinal Study in Taiwanese Traffic Conductors

BackgroundThere is accumulating epidemiologic evidence that exposure to traffic-related air pollutants, including particulate matter (PM) and polyaromatic hydro carbons (PAHs), plays a role in etiology and prognosis of a large scale of illnesses, although the role of specific causal agents and underlying mechanisms for different health outcomes remains unknown.ObjectiveOur general objective was to assess the relations between personal exposure to traffic exhausts, in particular ambient PM2.5 and PAHs, and the occurrence of DNA strand breaks by applying personal monitoring of PM and biomarkers of exposure (urinary 1-hydroxypyrene-glucuronide, 1-OHPG) and effect (urinary 8-hydroxydeoxyguanosine, 8-OHdG and DNA strand breaks).MethodsWe recruited 91 traffic conductors and 53 indoor office workers between May 2009 and June 2011 in Taipei City, Taiwan. We used PM2.5 personal samplers to collect breathing-zone particulate PAHs samples. Spot urine and blood samples after work shift of 2 consecutive days were analyzed for 1-OHPG, 8-OHdG and DNA strand breaks, respectively. Statistical methods included linear regression and mixed models.ResultsUrinary 8-OHdG levels and the occurrence of DNA strand breaks in traffic conductors significantly exceeded those in indoor office workers in mixed models. Particulate PAHs levels showed a positive association with urinary 1-OHPG in the regression model (β = 0.056, p = 0.01). Urinary 1-OHPG levels were significantly associated with urinary 8-OHdG levels in the mixed model (β = 0.101, p = 0.023). Our results provide evidence that exposure to fine particulates causes DNA damage. Further, particulate PAHs could be biologically active constituents of PM2.5 with reference to the induction of oxidative DNA damages.

Increased levels of 8-hydroxy-2′-deoxyguanosine are attributable to organophosphate pesticide exposure among young children

Oxidative damage has been proposed as an important mechanism linking pesticide exposure to health effects. A study of 268 young Shanghai children was conducted to examine the relationship between organophosphate pesticide (OP) exposure and a biomarker of oxidative DNA damage. Urine samples were analyzed for five nonspecific dialkyl phosphate (DAP) metabolites [dimethyl phosphates (DMs) and diethyl phosphates (DEs)] and 8-hydroxy-2′-deoxyguanosine (8-OHdG). The creatinine-adjusted median of 8-OHdG in urine samples was 3.99ng/mg. Increased exposure to OPs was associated with greater levels of urinary 8-OHdG [total DAPs: ß (adjusted)=0.46 per log10 unit increase, 95% confidence interval (CI)=0.40–0.53, p=0.000; DMs: ß (adjusted)=0.34, 95% CI=0.28–0.41, p=0.000; DEs: ß (adjusted)=0.48, 95% CI=0.42–0.54, p=0.000]. Thus, the 8-OHdG biomarker is useful for increasing our understanding of the link between childhood exposure to OPs and health outcomes.

Genotoxicity assessment in patients with thalassemia minor

Thalassemia is an inherited blood disorder that affects both genders and results in reduced synthesis of hemoglobin, and thus causing anemia. Previous studies have shown that the severe form of this disease, thalassemia major, is associated with genotoxicity. This includes increases in the level of sister chromatid exchange (SCEs), chromosomal aberrations (CAs) and micronuclei. In this study, we assessed genotoxicity in the lymphocytes of thalassemia minor subjects using sister chromatid exchange (SCE) and chromosomal aberration (CA) assays. In addition, we investigated the level of oxidative DNA damage by measuring 8-hydroxy-2′-deoxyguanosine (8OHdG) biomarker in urine samples. Eighteen thalassemia minor subjects and eighteen matched normal healthy controls were volunteered in the study. In addition, seven thalassemia major patients were recruited as positive controls. The results showed increases in the frequency of SCEs (P<0.05) in thalassemia minor compared to healthy controls. However, no difference in CAs frequency was detected between thalassemia minor and controls (P>0.05). Both SECs and CAs in thalassemia major patients were significantly higher compared to other groups (P<0.05). Regarding urine 8OHdG levels, the result showed a slight increase in thalassemia minor compared to healthy controls but the difference was not significant (P>0.05). In conclusion, our results showed that thalassemia minor is associated with genotoxicity to blood lymphocytes as indicated by SCEs assay.

Analysis of 8-hydroxy-2′-deoxyguanosine in human urine using hydrophilic interaction chromatography with tandem mass spectrometry

Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) is a widely used noninvasive biomarker of oxidative stress. A selective, sensitive and rapid method for determining 8-OHdG in human urine was developed using hydrophilic interaction chromatography–tandem mass spectrometry (HILIC–MS/MS) with electrospray ionization. 8-OHdG and isotopically labeled 8-OHdG (internal standard) were separated on a HILIC column with a mobile phase of 10mM ammonium acetate: acetonitrile (1:9, v/v) within 10min and detected by using a positive electrospray ionization interface under the selected reaction monitoring mode. The detection limits of 8-OHdG (corresponding to a signal-to-noise ratio of 3) for the HILIC-MS/MS system and the conventional method using a reversed-phase column with MS/MS were 1.0 and 26.0fmol/injection, respectively. The proposed method makes it possible to monitor the basal level of urinary 8-OHdG from non-exposed healthy subjects and can be used for large-scale human studies.

Telomere length shortening in patients with dementia with Lewy bodies

Shortened telomere length has been considered to be associated with various age-related diseases, especially in dementia such as Alzheimer's disease and vascular dementia. However, changes in telomere length in dementia with Lewy bodies (DLB) remain unclear. To elucidate these changes, we set out to determine telomere length in peripheral leukocytes as well as the level of urinary 8-hydroxy-deoxyguanosine (8-OHdG) as a marker of oxidative stress in DLB. Blood samples were obtained from 33 patients with a clinical diagnosis of probable DLB and 35 age-matched, non-demented elderly controls (NEC). Telomere length was assessed by quantitative real-time polymerase chain reaction of genomic DNA extracted from leukocytes, whereas oxidative stress was assessed on the basis of urine 8-OHdG level, which was measured using high-performance liquid chromatography. Telomere length was significantly shorter in the DLB group than in the NEC group. Urinary 8-OHdG levels were significantly higher in the DLB group than in the NEC group. There was a negative correlation between telomere length and age in the DLB group; however, there were no significant relationships between telomere length and clinical findings including disease duration, severity of cognitive decline, presence or absence of fluctuation in cognitive function, visual hallucinations, and Parkinsonism. In both groups, the correlation between telomere length and urinary 8-OHdG levels was not significant. These findings indicate that the etiopathology of DLB is considered to be an accelerated aging process.

Changes in Urinary Albumin Excretion, Inflammatory and Oxidative Stress Markers in ADPKD Patients with Hypertension

BackgroundsAutosomal dominant polycystic kidney disease (ADPKD) progresses more quickly to end-stage renal disease in patients with hypertension than in their normotensive counterparts. The authors investigated the effect of telmisartan versus enalapril on systolic and diastolic blood pressure (SBP and DBP), urinary albumin excretion (UAE), serum high mobility group box-1 protein (HMGB1), serum interleukin (IL)-6 and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels in patients with hypertensive ADPKD. MethodsTwenty patients with hypertensive ADPKD with good renal function were randomly assigned to 1 of 2 treatments: telmisartan 80mg once daily (n=10) or enalapril 10mg once daily (n=10). Treatment lasted 12months. SBP, DBP, serum creatinine, UAE, HMGB1, IL-6 and urinary 8-OHdG levels were measured before and 6 and 12months after treatment. ResultsBoth SBP and DBP were significantly reduced after treatment (P<0.001) in both groups. Serum creatinine changed little during the experimental period in either group. UAE, serum HMGB1, serum IL-6 and urinary 8-OHdG levels were significantly decreased after treatment (UAE, HMGB1 and IL-6, P<0.001; and 8-OHdG, P<0.01 versus baseline levels) in both groups. However, the decreases in UAE, serum HMGB1 and serum IL-6 were significantly greater in the telmisartan group than in the enalapril group at 6months (P<0.05, P<0.01 and P<0.01, respectively) and 12months (all, P<0.05). ConclusionsTelmisartan seems to be equivalent to enalapril in lowering BP, but telmisartan has more potent renoprotective, anti-inflammatory and antioxidative effects than enalapril in patients with hypertensive ADPKD.

Association between Urinary 8-Hydroxydeoxyguanosine, an Indicator of Oxidative Stress, and the Cardio-Ankle Vascular Index in Hypertensive Patients

Oxidative stress has been recently postulated to be an important factor in the pathogenesis and development of arteriosclerosis. Although urinary 8-hydroxydeoxyguanosine (8-OHdG) is clinically used as a marker of oxidative stress, its usefulness in diagnosing arteriosclerosis has not been fully examined. This study aimed to evaluate the association between urinary 8-OHdG and the cardioankle vascular index (CAVI) as a marker of arterial stiffness in hypertensive patients. We enrolled 100 hypertensive patients (70 ± 10 years) who had been taking antihypertensive medications for at least one year. Urinary 8-OHdG levels were measured by an immunochromatographic assay (ICR-001; Selista Inc., Tokyo, Japan). CAVIs were measured at the same visit. Urinary 8-OHdG was correlated with smoking habits (r=0.382, p<0.001) and CAVIs (r= 0.223, p= 0.026). Multiple linear regression analysis revealed two independent determinants of urinary 8-OHdG: smoking habits (β=0.501, p<0.001) and CAVI (β=0.325, p=0.001). In addition, CAVIs were correlated with age (r= 0.600, p<0.001), BMI (r=-0.348, p<0.001), systolic blood pressure (r= 0.343, p<0.001), pulse pressure (r= 0.358, p<0.001), serum creatinine level (r=0.408, p<0.001), urinary 8-OHdG level (r= 0.223, p= 0.026), and diabetes (r= 0.210, p=0.036). Multiple linear regression analysis revealed two independent determinants of CAVI: age (β= 0.568, p<0.001) and 8-OHdG (β=0.357, p<0.001). Elevated CAVI is independently associated with an elevated urinary 8-OHdG level in hypertensive patients.

A Novel Diabetes Mellitus Mouse Model, MAFA-Deficient and Beta Cell-Specific MAFK-Overexpressing Hybrid Transgenic Mice, Developed Severe Diabetic Nephropathy and Improved with TCV-116 (Candesartan Cilexetil) Treatment

Many models of diabetic nephropathy have been reported. However, it is rare that the characteristic findings of severe human diabetic nephropathy, such as diffuse, nodular, and exudative lesions, are all detected in one model mouse. Previously, we reported that MAFA-deficient and beta cell-specific MAFK-overexpressing hybrid transgenic (Mafa(-/-)Mafk (+)) mice develop diabetes mellitus and, after uninephrectomy, demonstrate these characteristic lesions. In this study, we administered TCV-116 (candesartan cilexetil) to Mafa(-/-)Mafk (+) mice after uninephrectomy and examined whether TCV-116 ameliorated the diabetic nephropathy. We also evaluated the utility of these mice as a model for developing treatments for diabetic nephropathy. We performed uninephrectomy of the Mafa(-/-)Mafk (+) mice at 8 weeks old. We then divided these mice into two groups as follows: 1) an untreated group and 2) a group treated with TCV-116 at 5 µg/g/day from 10 to 20 weeks. TCV-116 treatment did not affect serum glucose levels. However, in the treated group, urinary protein excretion, mesangial matrix expansion, enlargement of the kidney, and glomerular surface area were all improved relative to untreated mice. Oxidative stress is known to be increased in diabetic nephropathy and to be suppressed by TCV-116. The urinary level of 8-OHdG, an oxidative stress marker, at 20 weeks was lower in the TCV-116-treated group than in the untreated group. From these results, we concluded that the Mafa(-/-)Mafk (+) mouse is a useful model to analyze diabetic nephropathy and a useful tool for the development of new drugs to treat diabetic nephropathy.

Biomarkers of Oxidative Stress in Vascular Dementia Patients

Little is known about the role of oxidative stress in the pathogenesis of vascular dementia (VaD). The aim of this study was to investigate the biomarkers of oxidative stress in urine, as reflected by 8-hydroxydeoxyguanosine (8-OHdG), 8-isoprostaglandin F(2a) (8-isoPGF(2a)) and nitrotyrosine (NT) levels, in a group of well characterized VaD patients and in two control groups of Vascular Not Demented (VaND) patients and health y subjects. Ninety-six subjects from the Tianjin municipality in China were recruited. Forty-six patients were in the VaD group, 24 patients with VaND and 26 persons with no signs of cognitive disorder were employed as control groups. Urinary 8-OHdG and 8-isoPGF(2a) was performed using enzyme-linked immunosorbent assay (ELISA), and urinary NT levels were measured by chemiluminescence detection. Significantly higher urinary 8-OHdG levels were detected in VaD patients compared to VaND patients and healthy control subjects. In contrast, urinary 8-isoPGF(2a) levels were significantly lower in VaD patients compared with two control groups. For NT levels, no statistically significant differences were observed among the three groups. Increased urinary 8-OHdG level was a potential marker of oxidative stress in VaD patients. Furthermore, it is also important to take into account potential confounders in order to improve the identification of changes in the status of oxidative stress as related to VaD.