Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease

Abstract

In patients with uremia, increased blood concentrations of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) have been linked to the severity of atherosclerosis and to excess cardiovascular mortality. The ADMA levels and several traditional cardiovascular risk factors were assessed in 44 untreated nonsmoking patients with confirmed primary chronic renal disease at different stages of renal disease. True GFR was assessed by means of the inulin-clearance technique. For comparison, nonsmoking subjects matched with respect to age, gender, and body-mass index were examined. Mean plasma ADMA concentration was markedly higher (P < 0.0001) in all patients combined (4.2 ± 0.9 μmol/L) than in control subjects (n = 16; age 45 ± 10 yr; serum creatinine 1.0 ± 0.1 mg/dl; ADMA 1.4 ± 0.7 μmol/L). However, mean ADMA levels were similar in patients with normal renal function (n = 16; age 41 ± 9 yr; serum creatinine 1.1 ± 0.1 mg/dl; GFR 120 ± 14 ml·min-1·1.73 m2; ADMA 4.0 ± 0.7 μmol/L), in patients with moderate renal failure (n = 15; 47 ± 7 yr; 1.8 ± 0.3 mg/dl; 65 ± 10 ml·min-1·1.73 m2; 3.8 ± 0.6 μmol/L) and in patients with advanced renal failure (n = 13; 46 ± 9 yr; 4.2 ± 0.9 mg/dl; 25 ± 4 ml·min-1·1.73 m2; 4.7 ± 1.2 μmol/L). Furthermore, ADMA levels were increased to the same extent in normotensive (n = 17; 4.0 ± 0.8 μmol/L) and in hypertensive (n = 27; 4.2 ± 0.9 μmol/L) patients. In contrast to ADMA, mean total plasma homocysteine concentration were similar in control subjects (10.6 ± 2.9 μmol) and in patients with normal GFR (11.0 ± 2.9 μmol/L), but were significantly higher in patients with moderate renal failure (17.7 ± 4.1 μmol/L) and particularly in patients with advanced renal failure (28.2 ± 10.6 μmol/L). Finally, mean total serum cholesterol concentrations were comparable in the control group and in the three groups of patients with renal disease. In contrast to several traditional cardiovascular risk factors, markedly increased blood concentrations of ADMA, a putative biochemical marker of atherosclerosis, are present even in nonsmoking patients without diabetes with incipient primary renal disease. Thus, the early increase of ADMA levels may be of relevance for the excess cardiovascular morbidity and mortality due to arterio- and atherosclerotic complications in patients with renal disease.