Elevated Plasma Asymmetric Dimethylarginine as a Marker of Cardiovascular Morbidity in Early Diabetic Nephropathy in Type 1 Diabetes

Abstract

OBJECTIVE—Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. RESEARCH DESIGN AND METHODS—ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 μmol/l [range 52–684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). RESULTS—In patients with diabetic nephropathy, mean ± SD plasma ADMA concentration was elevated 0.46 ± 0.08 vs. 0.40 ± 0.08 μmol/l in normoalbuminuric patients (P < 0.001). An increase in plasma ADMA of 0.1 μmol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89–4.05) (P < 0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml · min–1 · 1.73 m–2) (P < 0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P > 0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 ± 0.08 μmol/l compared with 0.46 ± 0.08 μmol/l in patients without major cardiovascular events (P = 0.05). CONCLUSIONS—Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.