Plasma arginine metabolites in health and chronic kidney disease

Abstract

Background: Elevated plasma asymmetric and symmetric dimethylarginine (ADMA and SDMA) are risk factors for chronic kidney disease (CKD) and cardiovascular disease. Using plasma cystatin C (pCYSC)-based estimated glomerular filtration rate (eGFR) trajectories, we identified a cohort at high risk of poor kidney-related health outcomes amongst members of the Dunedin Multidisciplinary Health and Development Study (DMHDS). We therefore examined associations between methylarginine metabolites and kidney function in this cohort. Methods: ADMA, SDMA, L-arginine and L-citrulline were measured in plasma samples from 45-year-olds in the DMHDS cohort by liquid chromatography-tandem mass spectrometry. Results: In a healthy DMHDS subset (n = 376), mean concentrations were: ADMA (0.40 ± 0.06 μmol/L), SDMA (0.42 ± 0.06 μmol/L), L-arginine (93.5 ± 23.1 μmol/L) and L-citrulline (24.0 ± 5.4 μmol/L). In the total cohort (n = 857), SDMA correlated positively with serum creatinine (Pearson's r = 0.55) and pCYSC (r = 0.55), and negatively with eGFR (r = 0.52). A separate cohort of 38 patients with stage 3-4 CKD (eGFR 15-60 mL/min/1.73 m2) confirmed significantly higher mean ADMA (0.61 ± 0.11 μmol/L), SDMA (0.65 ± 0.25 μmol/L) and L-citrulline (42.7 ± 11.8 μmol/L) concentrations. DMHDS members classified as high-risk of poor kidney health outcomes had significantly higher mean concentrations of all four metabolites compared with individuals not at risk. ADMA and SDMA individually predicted high-risk of poor kidney health outcomes with areas under the ROC curves (AUCs) of 0.83 and 0.84, and together with an AUC of 0.90. Conclusions: Plasma methylarginine concentrations facilitate stratification for risk of CKD progression.