Homocysteine and Arginine-to-Asymmetric Dimethylarginine Ratio Associated With Blood Pressure Abnormalities in Children With Early Chronic Kidney Disease

Abstract

Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp (NO), a vasodilator, regulates endothelial function and blood pressure (BP). Our previous review indicated emerging evidence supporting that a deficiency of NO links endothelial dysfunction to CVD in pediatric CKD. 3 Because asymmetric dimethylarginine (ADMA) is an analog of L-arginine (ARG), the substrate for NO synthase (NOS), the ARG-to-ADMA ratio (AAR) represents NO bioavailability and maintains NO homeostasis. 4 Elevated plasma ADMA levels are observed in patients with hypertension (HT) as well as CKD. 5,6 Ambulatory BP monitoring (ABPM) has proven to be the best method of detecting abnormal BP and cardiovascular outcome in CKD. 7 Our recent reports showed that ARG metabolites in the NO pathway are interrelated and involved in abnormal ABPM profiles in children with CKD. 8,9 ADMA is synthesized by the ardiovascular disease (CVD) is a major cause of morbidity and mortality in children and adults with chronic kidney disease (CKD). 1 Unlike adults, young CKD patients rarely present with CV events. Thus assessment of CVD in childhood mainly relies on the characteristics of vascular phenotype. Less attention has been paid to evaluating subclinical CVD in the early stage of CKD in the pediatric population. It is noteworthy that CKD children with subclinical CVD are at risk of subsequent development of CVD in adulthood. Thus, identification of surrogate markers to detect subclinical CVD in early CKD children may aid in reducing the global burden of CKD.Deterioration in endothelial function and arterial stiffness are early events in the development of CVD. Background: Less attention has been paid to evaluating subclinical cardiovascular disease (CVD) in the early stage of pediatric chronic kidney disease (CKD). Ambulatory blood pressure monitoring (ABPM) and arterial stiffness are the earliest detectable assessments of subclinical CVD. Asymmetric dimethylarginine (ADMA) is an analog of L-arginine (ARG) that inhibits nitric oxide (NO) production; thus the ARG-to-ADMA ratio (AAR) is an index of NO. Homocysteine (HCY) is a risk factor for CVD and it can be metabolized to L-cysteine (CYS). Given that HCY and ADMA/NO are closely linked and related to hypertension, we therefore investigated whether ARG and HCY metabolites, arterial stiffness parameters, ABPM profile, and left ventricular hypertrophy (LVH) are interrelated in children and adolescents with early CKD.

Asymmetric dimethylarginine is not a marker of arterial damage in children with glomerular kidney diseases

“…This discrepancy may be due to the fact that only small subgroup of our subjects showed mild to moderate impairment of renal function and we excluded patients with CKD stages 4 and 5. Similarly to our results, no difference was found in terms of ADMA level between pediatric patients with normal kidney function and CKD stages 2 and 3 [16].…”

“…Although ADMA was significantly and independently associated with cIMT in a group of 405 8-year-old Australian children [39], this relation was not confirmed in high-risk patients. ADMA level did not correlate with cIMT in pediatric patients with primary hypertension [14], with cIMT, PWV, and ambulatory arterial stiffness index (AASI) in children with CKD stages 1-3 [16], with cIMT in children with CKD stages 2-5 [17], or with cIMT, PWV, and AIx75HR in children with juvenile idiopathic arthritis [15].…”

“…Numerous studies in adult population showed positive relation between ADMA and both intermediate end-points [7,8] as well as cardiovascular morbidity and mortality [11,12]. There are limited data on usefulness of ADMA assessment in children with nephrotic syndrome [13], hypertension [14], juvenile idiopathic arthritis [15], and chronic kidney disease [16,17].…”

Oxidative stress in chronic kidney disease

“…There is plenty of evidence for increasing levels of OS markers with deteriorating renal function, beginning from early CKD stages [11] in both adults and children. Like in adults, data from children and young adults with CKD show increasing concentrations of OS markers such as mitochondrial superoxide and oxidized LDL [90][91][92], homocysteine [93], as well as a deficiency of SOD and GSH [91,92] together with disease progression. Also, several uremic toxins, associated with increased OS in CKD, increase with worsening renal function, such as the retention solute IS [94], F 2 -isoprostanes, MDA, and ADMA [95,96].…”

Homocysteine and hydrogen sulfide in epigenetic, metabolic and microbiota related renovascular hypertension

“…On the other hand, in a prospective study the progression of blood pressure on normotensive population over 2-years period Wang et al found that homocysteine is related to hypertension incidence at high levels, and may also increase the risk of hypertension at low levels [142]. Children with early CKD showed blood pressure abnormalities, mostly having a positive correlation with high homocysteine levels along with other factors, in a cross-sectional study [143]. Nevertheless, none of these studies provided strong evidences that the homocysteine causes human hypertension [137, 144].…”