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

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

mlaj{at}steno.dk

ABSTRACT

Objective: To investigate whether circulating ADMA levels are predictive of cardiovascular events, decline in glomerular filtration rate (dGFR), end-stage renal disease (ESRD), and all-cause mortality in type 1 patients.

Research Design and Methods: A prospective observational follow-up study; including 397 type 1 patients with overt diabetic nephropathy (243 men; age 42.1 ± 10.5 years (mean ± SD); GFR 76 ± 34 ml/min/1.73 m²) and a control group of 175 patients with longstanding type 1 and persistent normoalbuminuria (104 men; age 42.7 ± 9.7 years; duration of diabetes 27.7 ± 8.3 years). Patients were followed for 11.3 (0.0-12.9) years (median (range)) with yearly measurements of GFR (⁵¹Cr-EDTA plasma clearance) in patients with diabetic nephropathy. Endpoints were fatal and non-fatal CVD, dGFR, ESRD, and all-cause mortality.

Results: Among patients with diabetic nephropathy, 37 (19.4 %) patients with ADMA levels below the median compared to 79 (43.4 %) patients 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 of 2.05 (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 HR (adjusted) was 1.85 (0.99; 3.46); p= 0.055 for ESRD comparing upper and lower median ADMA levels.

Conclusions: Plasma ADMA levels predict fatal and non-fatal cardiovascular events in patients with type 1 nephropathy. Furthermore, increased ADMA levels tended to contribute to increased risk of progressive diabetic kidney disease.

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