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Plasma Concentration of Asymmetric Dimethylarginine (ADMA) Predicts Cardiovascular Morbidity and Mortality in Type 1 Diabetic Patients With Diabetic Nephropathy

¹ Steno Diabetes Center, Gentofte, Denmark
² Department of Clinical Chemistry, VU, University Medical Center, Amsterdam, the Netherlands
³ Department of Medical Endocrinology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
⁴ Faculty of Health Science, University of Aarhus, Aarhus, Denmark

Address correspondence and reprint requests to Maria Lajer, Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark. E-mail: mlaj{at}steno.dk

OBJECTIVE—To investigate whether circulating asymmetric dimethylarginine (ADMA) levels are predictive of cardiovascular events, decline in glomerular filtration rate (GFR), end-stage 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 1 diabetic patients with overt diabetic nephropathy (243 men aged 42.1 ± 10.5 years, GFR 76 ± 34 ml/min per 1.73 m²) and a control group of 175 patients with longstanding type 1 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 (⁵¹Cr-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 1.31–3.20], 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 1 diabetic nephropathy. Furthermore, increased ADMA levels tend to contribute to increased risk of progressive diabetic kidney disease.

Abbreviations: ADMA, asymmetric dimethylarginine • AHT, antihypertensive treatment • CVD, cardiovascular disease • DDAH, dimethylarginine dimethylaminohydrolases • ESRD, end-stage renal disease • GFR, glomerular filtration rate • SDC, Steno Diabetes Center • SDMA, symmetrical dimethylarginine

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