8-hydroxyguanosine and Albuminuria

The RNA oxidation product, 8-oxo-7,8-dihydroguanosine (8-oxoGuo), has been associated with mortality in patients with type 2 diabetes (T2D). However, the identification and the potential effect of approved treatments decreasing urine 8-oxoGuo level remain unraveled. In the Steno-2 study intensified multifactorial treatment compared with conventional multifactorial treatment reduced mortality in T2D patients with microalbuminuria by 45%. We assessed association between 8-oxoGuo at advanced baseline and total mortality with up to 19.9 years follow-up and from end of intervention to end of follow-up up to (up to 13.9 years).. In 1993, 160 T2D patients with microalbuminuria were included in the Steno-2 trial. Urine samples from baseline were not available, but samples were available from 155 patients (97%) in 1995 (advanced baseline) and from 125 patients (96%) in 2001 (end of intervention). Hazard ratios (HR) for log2-transformed 8-oxoGuo and dichotomized (cut-off at median; low vs. high RNA oxidation) were estimated using Cox regressions.. During follow-up of 19.9 years after advanced baseline, 89 died and no association between 8-oxoGuo and mortality was found (p = 0.40). From the end of 7.8 years of intervention and during remaining 13.9 years of observation, 61 died and doubling the urine 8-oxoGuo level was associated with mortality with a HR 3.08 (95% CI [1.86 -5.12]; p < 0.001) after multiple adjustments. Patients with low 8-oxoGuo in the intensified-treatment had the lowest risk of dying compared with high 8-oxoGuo in the conventional-treatment both from advanced baseline onwards, adjusted HR 0.40 (95% CI [0.21 -0.75]; p = 0.004), and from end of intervention onwards, adjusted HR 0.28 (95% CI [0.13 -0.61]; p = 0.001).. In T2D patients with microalbuminuria, high levels of urine 8-oxoGuo after 7.8 years of multifactorial intervention was associated with higher mortality during 13.9 years of post-trial follow-up. Patients with low 8-oxoGuo in the intensified treatment group had the lowest risk of dying.

Topics: Aged; Albuminuria; Biomarkers; Combined Modality Therapy; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Longitudinal Studies; Male; Middle Aged; Oxidation-Reduction; Prognosis; RNA; Survival Analysis

Urinary albumin is an important biomarker used to identify high risk patients with diabetes, but there is a need for new biomarkers that alone or in combination with urinary albumin could give an even better prediction of clinical patient outcomes. One promising biomarker is 8-oxo-7,8-dihydroguanosine (8-oxoGuo) that represents intracellular oxidative stress. We investigated the ability of microalbuminuria (MA) and urinary 8-oxoGuo, alone and in combination, to predict mortality and cardiovascular disease (CVD) in patients with type 2 diabetes. We used data from 1381 newly diagnosed diabetes patients, and urinary albumin and 8-oxoGuo were assessed in morning urine collected at the time of diabetes diagnosis and at a follow-up visit 6 years later. Associations between the urinary markers and mortality and CVD were assessed in Cox proportional hazards regression models. Test performance was assessed using sensitivity, specificity, positive predictive value and negative predictive value for 10-year mortality and 10-year incidence of CVD. Both 8-oxoGuo and urinary albumin were statistically significantly associated with all-cause mortality at diagnosis as well as at 6-year follow-up. At diagnosis only urinary albumin was associated with CVD. In contrast, only 8-oxoGuo was associated with CVD at 6-year follow-up. When investigating test performance, we found that by combining information from MA and 8-oxoGuo the ability to correctly identify patients at risk could be improved. The findings suggest that measurement of urinary 8-oxoGuo provides additional information about risk to that obtained from urinary albumin, and that the combined use of 8-oxoGuo and urinary albumin could be useful for a better identification of patients at risk of CVD and death.

Topics: Aged; Albuminuria; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Guanosine; Humans; Male; Middle Aged