Modulation of endogenous antioxidant defense and the progression of kidney disease in multi-heritage groups of patients with type 2 diabetes: PRospective EValuation of Early Nephropathy and its Treatment (PREVENT)

Abstract

BackgroundDiabetes is the western world’s leading cause of end-stage renal disease. Glucose-dependent, oxidative stress is linked to the development of renal inflammation and sclerosis, which, in animal models of diabetes, can be prevented by anti-oxidative treatment. Patients of non-Caucasian heritage have low activity of the selenoprotein, antioxidant enzyme, glutathione peroxidase (GPx) and its co-factor vitamin E, which may be linked to their increased propensity to developing end-stage renal disease.Research design and methodsWe have designed a double-blind, randomized, placebo controlled study with selenium and/or vitamin E versus placebo as the interventions for patients with type 2 diabetes and chronic kidney disease (CKD) stages 1–3. A 2 × 2 factorial design will allow a balanced representation of the heritage groups exposed to each intervention. The primary biochemical outcome is change in GPx activity, and clinical outcome measure is the actual, rate of—and/or percentage change in estimated glomerular filtration rate (eGFR) from baseline. Analysis will be with a marginal model for longitudinal data using Generalized Estimating Equations corrected for measures of baseline serum antioxidant enzyme activities (GPx, superoxide dismutase and catalase), micronutrient levels (vitamins E and C), measures of inflammation (interleukin 6, c-reactive protein and monocyte chemoattractant protein-1) and markers of oxidative damage (plasma 8-isoprostaglandin F2α and urinary 8-hydroxydeoxyguanosine).Expected resultsThe study will assess the relationship between GPx activity, oxidative stress, inflammation and eGFR. It will test the null hypothesis that antioxidant therapy does not influence the activity of GPx or other antioxidant enzymes and/or alter the rate of change in eGFR in these patient groups.ConclusionsOutcome data on the effect of antioxidants in human diabetic renal disease is limited. Previous post hoc analyses have not shown a beneficial effect of vitamin E on renal function. A recent trial of a pharmaceutical antioxidant agent, improved eGFR, but in patients with advanced diabetes-related chronic kidney disease its use was associated with an increased incidence of cardiovascular events. We will explore whether the nutritional antioxidants, vitamin E and selenium alone, or in combination in patients at high risk of renal disease progression, forestalls a reduction in eGFR. The study will describe whether endogenous antioxidant enzyme defenses can be safely modified by this intervention and how this is associated with changes in markers of oxidative stress.Trial registration ISRCTN 97358113. Registered 21st September 2009

Effectiveness and safety of selenium supplementation for type 2 diabetes mellitus in adults: a systematic review of randomised controlled trials

“…For the characteristics of excluded trials, with reasons for their exclusion, see the Supporting information (Table S3). Moreover, two registered RCTs were identified (one RCT completed, with published study protocol) , although the results were not available (see the Supporting information, Table S4).…”

Dietary Total Antioxidant Capacity and Its Association with Renal Function and Progression of Chronic Kidney Disease in Older Adults: a Report from a Developing Country

“…Bonaccio et al [ 26 ], also reported that adherence to a Mediterranean diet is along with a high intake of antioxidant components like MUFA, fiber, folate, and vitamin E. In a population-based cohort study, a higher intake of vitamin E and vitamin C had associated with reduced risk incidence of CKD. Apart from observational studies, these reported associations have been confirmed in a few intervention studies with improvement in eGFR and protein excretion following a pharmacological dose of vitamins C and E [ 27 ], which was not confirmed in others [ 28 ]. The consumption of fibers from fruits, vegetables, and whole grains, confirms a higher intake of nutrients found in these foods like folate and vitamin C. It also showed a relation between dietary fiber with a reduction of inflammation and mortality among patients with CKD [ 29 ].…”

Sex Differences in Glutathione Peroxidase Activity and Central Obesity in Patients with Type 2 Diabetes at High Risk of Cardio-Renal Disease

“…We studied a cohort of 170 adult men and women with type 2 diabetes mellitus who were recruited as part of the PREVENT trial from general practices in South West London, UK (protocol previously published, Trial Registration ISRCTN 97358113 [25]. Written informed consent was obtained from all participants prior to inclusion in the study and ethical permission was granted by the National Health Service Ethics Research Committee (05/Q0803/57).…”