Methylated arginine derivatives in children and adolescents with chronic kidney disease

Asymmetric dimethylarginine (ADMA), a methylated L-arginine (Arg) derivative is associated with endothelial dysfunction, vasoconstriction, and hypertension in animals and humans. We examined the relationship between these derivatives, estimated glomerular filtration rate (eGFR), and awake (AW) and asleep (AS) blood pressure (BP) load in children and adolescents (n=28) with stage 2-3 chronic kidney disease (CKD) and in matched intra-familial controls (n=10). Plasma L-Arg, ADMA, and symmetric dimethylarginine (SDMA) levels were measured by high-performance liquid chromatography-tandem mass spectrometry. Subjects wore a 24-hr ambulatory BP monitor with BP load >95th percentile. ADMA, SDMA/ADMA ratio and SDMA were 38-200% higher in CKD patients while L-Arg/ADMA and L-Arg/SDMA ratios and the L-Arg level were 11-64% lower. The eGFR explained 42-60% of L-Arg/SDMA, SDMA/ADMA, and SDMA variability (n=38). Using linear regression, SDMA and SDMA/ADMA separately explained 15-38% of AW and AS systolic (S) BP and diastolic (D) BP load variability (p<0.001-0.022). Using multivariate stepwise regression with eGFR held constant, SDMA/ADMA was a significant independent variable for AW DBP load (p=0.03). In conclusion, BP load and a disproportionate elevation of SDMA are seen in children and adolescents with stage 2-3 (mild-moderate) CKD. SDMA is a strong marker for reduced eGFR and serves as a moderate but significant indicator of 24-hr BP load variability.