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

  1. Maria Lajer, MSC1,
  2. Lise Tarnow, DMSC1,
  3. Anders Jorsal1,
  4. Tom Teerlink, DMSC2,
  5. Hans-Henrik Parving, DMSC34 and
  6. Peter Rossing, DMSC1
  1. 1Steno Diabetes Center, Gentofte, Denmark
  2. 2Department of Clinical Chemistry, VU, University Medical Center, Amsterdam, the Netherlands
  3. 3Department of Medical Endocrinology, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark
  4. 4Faculty of Health Science, University of Aarhus, Aarhus, Denmark
  1. Address correspondence and reprint requests to Maria Lajer, Steno Diabetes Center, Niels Steensens Vej 1, 2820 Gentofte, Denmark. E-mail: mlaj{at}steno.dk

Abstract

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.

Footnotes

  • Published ahead of print at http://care.diabetesjournals.org on 27 December 2007. DOI: 10.2337/dc07-1762.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

    • Accepted December 17, 2007.
    • Received September 7, 2007.
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  1. Published online before print December 27, 2007, doi: 10.2337/dc07-1762 Diabetes Care April 2008 vol. 31 no. 4 747-752
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