Low urinary citrulline/arginine ratio associated with blood pressure abnormalities and arterial stiffness in childhood chronic kidney disease

Arginine (ARG) and citrulline (CIT) are essential for nitric oxide (NO) synthesis. Their metabolites are interrelated, and involved in blood pressure (BP) control, chronic kidney disease (CKD), and cardiovascular disease (CVD). Although CVD is the leading cause of mortality in CKD, little is known about subclinical CVD in early-stage childhood CKD. Twenty-four-hour ambulatory BP monitoring and arterial stiffness assessment allows the earlier possible detection of subclinical CVD. We investigated whether urinary CIT and ARG metabolites and their ratios are correlated with BP load and vascular abnormalities in children and adolescents with early-stage CKD. We enrolled 55 pediatric patients with mild-to-moderate CKD. Seventy percent (30/43) had at least one out of BP load abnormality on ambulatory BP monitoring, mainly increased asleep systolic BP (SBP) load (40%), asleep SBP or diastolic BP load > 95th percentile (40%), and nocturnal SBP nondipping (35%). Low urinary CIT level and CIT/ARG ratio were associated with BP load abnormalities in children with early CKD. Urinary CIT/ARG ratio was correlated with arterial stiffness, represented as pulse-wave velocity and augmentation index. SBP and diastolic BP loads were negatively correlated with urinary CIT, ARG, asymmetric dimethylarginine (an endogenous NO synthase inhibitor), and CIT/ARG ratio, while positively associated with dimethylamine/asymmetric dimethylarginine ratio and pulse-wave velocity. Early assessments of BP load abnormalities, urinary biomarkers in the CIT-ARG-NO pathway, and arterial stiffness parameters should increase early preventive care toward decreasing hypertension and CV remodeling in pediatric CKD.