Plasma concentration of asymmetric climethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy

OBJECTIVE - To investigate whether circulating asymmetric dimethylarginine (ADMA) levels are predictive of cardiovascular events, decline in glomerular filtration rate (GFR), endstage renal disease (ESRD), and all-cause mortality in type 1 diabetic patients. RESEARCH DESIGN AND METHODS - We performed a prospective observational follow-up study including 397 type I diabetic patients with overt diabetic nephropathy (243 men aged 42.1 +/- 10.5 years, GFR 76 +/- 34 ml/min per 1.73 m(2)) and a control group of 175 patients with longstanding type I diabetes and persistent normoalbuminuria (104 men aged 42.7 +/- 9.7 years, duration of diabetes 27.7 +/- 8.3 years). Patients were followed for a median 11.3 years (range 0.0-12.9) with yearly measurements of GFR (Cr-51-EDTA plasma clearance) in patients with diabetic nephropathy. Endpoints were fatal and nonfatal cardiovascular disease (CVD), decline in GFR, ESRD, and all-cause mortality. RESULTS - Among patients with diabetic nephropathy, 37 patients (19.4%) with ADMA levels below the median, compared with 79 patients (43.4%) above the median, suffered a major cardiovascular event during the follow-up period (P < 0.001). This effect persisted after adjustment for conventional CVD risk factors including baseline GFR (adjusted hazard ratio [HR] for elevated ADMA 2.05 [95% CI 1.31-3.201, P = 0.002). Furthermore, elevated ADMA levels predicted an increased rate of decline in GFR, development of ESRD, and all-cause mortality (P < 0.001). After adjustment for well-known progression promoters, including baseline GFR, the HR (adjusted) was 1.85 (95% CI 0.99-3.46, P = 0.055) for ESRD comparing upper and lower median ADMA levels. CONCLUSIONS - Plasma ADMA levels predict fatal and nonfatal cardiovascular events in patients with type I diabetic nephropathy. Furthermore, increased ADMA levels tend to contribute to increased risk of progressive diabetic kidney disease.