Biological variation of asymmetric dimethylarginine and related arginine metabolites and analytical performance goals for their measurement in human plasma

Background Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase which is believed to be a cause of endothelial dysfunction and has been shown to predict the occurrence of acute coronary events. Data regarding the biological variation of arginine and its methylated derivatives are conspicuously absent from the literature. Such data are important in setting analytical quality specifications, assessing the utility of population reference intervals and assessing the significance of changes in serial results from an individual. Materials and methods Arginine, homoarginine, ADMA and symmetric dimethylarginine (SDMA) are measured in plasma by high performance liquid chromatography. Twelve healthy volunteers underwent weekly blood sampling for 20 weeks in order to determine the intra- and inter-individual biological variation of these analytes, from which analytical quality specifications, indices of individuality (II) and reference change values (RCV) are derived. Plasma samples from 100 healthy individuals were obtained in order to determine population reference intervals. Results ADMA and symmetric dimethylarginine (SDMA) exhibit low intra-individual biological variation of 7.4% and 5.8%, respectively, imposing desirable imprecision goals (CVA) of <= 3.7% and 2.9% for these analytes. The described methodology achieves these goals, with analytical CVs of < 3.5% for all analytes. Goals for bias and total error were 3.1-10.1% and 7.2-16.0%, respectively. Reference intervals for ADMA and SDMA were 0.29-0.63 mu mol L-1 and 0.24-0.55 mu mol L-1, but have IIs < 1. RCVs were at least 20% for all analytes studied. Conclusions Dimethylarginine concentrations are tightly controlled in health, with the result that imprecision goals for laboratory methods require to be low. Relatively large differences are required between serial results to denote a significant change. Population reference intervals for dimethylarginines are likely to be of limited value in detecting 'abnormality' in an individual from a single result.