Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes

Background. Nitric oxide (NO) is thought to play an important role in the pathogenesis of diabetic nephropathy. We conducted a prospective, observational cohort study to explore the relationship between plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, and the development and progression of nephropathy in patients with type 2 diabetes. Methods. This was a hospital-based observational cohort study in Japanese type 2 diabetic patients with normoalbuminuria [urinary albumin-to-creatinine ratio (ACR) < 30 mg/g creatinine] or microalbuminuria (30 <= ACR < 300 mg/g creatinine). The primary endpoint was the development or progression of diabetic nephropathy, based on transition from any given stage to a more advanced stage of albuminuria. Results. We studied 225 diabetic patients, 81 women and 144 men, with a mean (+/- SD) age of 64 +/- 10 years. The majority (183) of patients were normoalbuminuric, with the remainder microalbuminuric (42). During the median follow-up period of 5.2 years, 27 normoalbuminuric and 10 microalbuminuric patients reached the primary endpoint. When patients were separated according to the median ADMA level (0.46 mu mol/l), patients with higher ADMA levels had a greater incidence of reaching the endpoint (P = 0.014 by the log-rank test). In the multivariate Cox proportional hazard model, the hazard ratio for reaching the endpoint for patients with higher versus lower ADMA levels was 2.72 (95% confidence interval 1.25-5.95; P = 0.012). Conclusions. Higher plasma levels of ADMA may be a novel and potent predictor of the progression of nephropathy in adult Japanese type 2 diabetic patients.