Relationship between Markers of Endothelial Dysfunction, Oxidant Injury and Tubular Damage in Patients with Insulin-Dependent Diabetes Mellitus

Abstract

1. Diabetic nephropathy is a serious microvascular complication in patients with insulin-dependent diabetes mellitus, resulting in end-stage renal disease in 30–45% of such patients. Despite intensive investigation, the pathophysiology of diabetic renal disease has not been fully elucidated. However, several clinical and experimental studies have suggested that endothelial dysfunction and free-radical activity may be important factors. 2. Forty normotensive patients with insulin-dependent diabetes mellitus of between 10 and 20 years duration with persistent normoalbuminuria (albumin excretion <30 mg/day) and normal renal function were investigated for markers of endothelial dysfunction (plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity), free oxygen radical generation (erythrocytic superoxide dismutase and glutathione peroxidase) and oxidant injury (serum malondialdehyde). Glomerular proteinuria (albuminuria, transferrinuria), tubular proteinuria (retinol-binding protein) and tubular enzymuria (N-acetyl glucosaminidase and leucine aminopeptidase) were also measured. 3. Patients were divided into two groups. Group 1 comprised 21 patients with elevated markers of endothelial dysfunction, and group 2 comprised 19 patients with normal levels of plasma von Willebrand factor, soluble thrombomodulin and angiotensin-converting enzyme activity. Thirty-eight healthy subjects matched for age and sex acted as controls. 4. Groups 1 and 2 were similar in age, sex, body weight, duration of diabetes mellitus and recent glycaemic control. Serum cholesterol, serum creatinine and glomerular proteinuria were similar in the three groups. Group 1 patients had significantly increased oxidant injury, tubular enzymuria and proteinuria compared with group 2 patients and control subjects (P <0.01). Erythrocytic glutathione peroxidase was significantly lower in group 1 compared with the other groups (P <0.01) and erythrocytic superoxide dismutase was lower in both diabetic groups compared with normal control subjects (P <0.01). Serum malondialdehyde, tubular enzymuria and proteinuria were comparable in group 2 patients with control subjects. 5. We conclude that endothelial dysfunction, oxidant injury and renal tubular damage may precede microalbuminuria in diabetic nephropathy. These data support the hypothesis that endothelial dysfunction first affects the postglomerular microvessels. It is associated with oxidant injury and renal tubular damage, which may be factors in the initiation of diabetic nephropathy.