{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T06:03:25Z","timestamp":1785477805007,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2019,10,24]],"date-time":"2019-10-24T00:00:00Z","timestamp":1571875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kaohsiung Chang Gung Memorial Hospital, Taiwan","award":["CORPG8F1031, CORPG8F1032, and CORPG8F1033"],"award-info":[{"award-number":["CORPG8F1031, CORPG8F1032, and CORPG8F1033"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiovascular disease (CVD) is common in chronic kidney disease (CKD), while major CV events are rare in young CKD patients. In addition to nitric oxide (NO)-related biomarkers, several surrogate markers have been assessed to stratify CV risk in youth with CKD, including 24-h ambulatory blood pressure monitoring (ABPM), carotid artery intima-media thickness (cIMT), pulse wave velocity (PWV), ABPM-derived arterial stiffness index (AASI), flow-mediated dilatation (FMD), and left ventricular mass index (LVMI). The aim of this study was to identify subclinical CVD through the analysis of indices of CV risk in children and adolescents with CKD. Between 2016 and 2018, the prospective observational study enrolled 125 patients aged 3 to 18 years with G1\u2013G4 CKD stages. Close to two-thirds of young patients with CKD exhibited blood pressure (BP) abnormalities on ABPM. CKD children with abnormal office BP showed lower plasma arginine levels and arginine-to-asymmetric dimethylarginine (ADMA) ratio, but higher ratios of ADMA-to-symmetric dimethylarginine (SDMA) and citrulline-to-arginine. High PWV and AASI, indices of arterial stiffness, both strongly correlated with high BP load. Additionally, LV mass and LVMI exhibited strong correlations with high BP load. Using an adjusted regression model, we observed the citrulline-to-arginine ratio was associated with 24-h systolic and diastolic BP, systolic blood pressure (SBP) load, and diastolic blood pressure (DBP) load. Early assessments of NO-related parameters, BP load abnormalities, arterial stiffness indices, and LV mass will aid in early preventative care toward decreasing CV risk later in life for children and adolescents with CKD.<\/jats:p>","DOI":"10.3390\/ijms20215301","type":"journal-article","created":{"date-parts":[[2019,10,25]],"date-time":"2019-10-25T04:41:27Z","timestamp":1571978487000},"page":"5301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7470-528X","authenticated-orcid":false,"given":"Chien-Ning","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan"},{"name":"School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Chen","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao-Hung","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Chun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-6407","authenticated-orcid":false,"given":"You-Lin","family":"Tain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kaohsiung 833, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1161\/HYPERTENSIONAHA.109.192639","article-title":"Noninvasive assessment of subclinical atherosclerosis in children and adolescents: Recommendations for standard assessment for clinical research: A scientific statement from the American Heart Association","volume":"54","author":"Urbina","year":"2009","journal-title":"Hypertension"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1681\/ASN.2011111115","article-title":"Cardiovascular disease in children with chronic kidney disease","volume":"23","author":"Mitsnefes","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1056\/NEJMoa031643","article-title":"Long-term survival of children with end-stage renal disease","volume":"350","author":"McDonald","year":"2004","journal-title":"N. Eng. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Hsu, C.N., and Tain, Y.L. (2019). Regulation of nitric oxide production in the developmental programming of hypertension and kidney disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030681"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"R913","DOI":"10.1152\/ajpregu.00250.2005","article-title":"Oxidative stress and nitric oxide deficiency in the kidney: A critical link to hypertension?","volume":"89","author":"Wilcox","year":"2005","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1097\/MNH.0b013e32834d54ca","article-title":"Nitric oxide synthase derangements and hypertension in kidney disease","volume":"21","author":"Baylis","year":"2012","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_8","first-page":"813","article-title":"Participation of nitric oxide in different models of experimental hypertension","volume":"57","year":"2008","journal-title":"Physiol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3360001","article-title":"Arginine metabolism: Nitric oxide and beyond","volume":"336","author":"Wu","year":"1998","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Hsu, C.N., and Tain, Y.L. (2019). Impact of arginine nutrition and metabolism during pregnancy on Offspring outcomes. Nutrients, 11.","DOI":"10.3390\/nu11071452"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/S0026-0495(97)90002-0","article-title":"Amino acid handling in uremic rats: Citrulline, a reliable marker of renal insufficiency and proximal tubular dysfunction","volume":"46","author":"Levillain","year":"1997","journal-title":"Metabolism"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1172\/JCI109771","article-title":"Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency","volume":"65","author":"Tizianello","year":"1980","journal-title":"J. Clin. Invest."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/0140-6736(92)90865-Z","article-title":"Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure","volume":"339","author":"Leone","year":"1992","journal-title":"Lancet"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Tain, Y.L., and Hsu, C.N. (2017). Toxic dimethylarginines: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Toxins, 9.","DOI":"10.3390\/toxins9030092"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Schlesinger, S., Sonntag, S.R., Lieb, W., and Maas, R. (2016). Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: A systematic review and meta-analysis of prospective studies. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165811"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jash.2015.11.008","article-title":"Low urinary citrulline\/arginine ratio associated with blood pressure abnormalities and arterial stiffness in childhood chronic kidney disease","volume":"10","author":"Lin","year":"2016","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00467-008-0972-1","article-title":"Methylated arginine derivatives in children and adolescents with chronic kidney disease","volume":"24","author":"Brooks","year":"2009","journal-title":"Pediatr. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1681\/ASN.2009060609","article-title":"Masked hypertension associates with left ventricular hypertrophy in children with CKD","volume":"21","author":"Mitsnefes","year":"2010","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.2215\/CJN.03130312","article-title":"Carotid intima-media thickness in children with CKD: Results from the CKiD study","volume":"7","author":"Brady","year":"2012","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1097\/01.mnh.0000441153.40072.e0","article-title":"Arterial stiffness in chronic kidney disease: An update","volume":"23","author":"Taal","year":"2014","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1161\/CIRCULATIONAHA.106.652859","article-title":"Endothelial function and dysfunction: Testing and clinical relevance","volume":"115","author":"Deanfield","year":"2007","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1097\/HJH.0000000000001039","article-title":"2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents","volume":"34","author":"Lurbe","year":"2016","journal-title":"J. Hypertens."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1053\/j.ajkd.2012.07.018","article-title":"CKiD (CKD in children) prospective cohort study: A review of current findings","volume":"60","author":"Wong","year":"2012","journal-title":"Am. J. Kidney Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s00467-016-3325-5","article-title":"Clinical characteristics and prevalence of complications of chronic kidney disease in children: The Taiwan Pediatric Renal Collaborative study","volume":"31","author":"Chou","year":"2016","journal-title":"Pediatr. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.1007\/s00467-006-0175-6","article-title":"Utility of ambulatory blood pressure monitoring in children and adolescents","volume":"21","author":"Graves","year":"2006","journal-title":"Pediatr. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1161\/HYPERTENSIONAHA.118.11390","article-title":"Involvement of arterial stiffness and Inflammation in hyperuricemia-related development of hypertension","volume":"72","author":"Tomiyama","year":"2018","journal-title":"Hypertension"},{"key":"ref_27","first-page":"999","article-title":"Uric acid and the kidney","volume":"29","author":"Cramer","year":"2004","journal-title":"Pediatr. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1172\/JCI7199","article-title":"Arginine, citrulline, and nitric oxide metabolism in end-stage renal disease patients","volume":"105","author":"Lau","year":"2000","journal-title":"J. Clin. Invest."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.pharmthera.2007.03.002","article-title":"The l-arginine paradox: Importance of the l-arginine\/asymmetrical dimethylarginine ratio","volume":"114","author":"Scalera","year":"2007","journal-title":"Pharm. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.earlhumdev.2014.01.010","article-title":"Advanced intrauterine growth restriction is associated with reduced excretion of asymmetric dimethylarginine","volume":"90","author":"Bassareo","year":"2014","journal-title":"Early Hum. Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1111\/j.1600-079X.2010.00806.x","article-title":"Melatonin prevents hypertension and increased asymmetric dimethylarginine in young spontaneous hypertensive rats","volume":"49","author":"Tain","year":"2010","journal-title":"J. Pineal Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s00392-017-1172-4","article-title":"Symmetric dimethylarginine (SDMA) outperforms asymmetric dimethylarginine (ADMA) and other methylarginines as predictor of renal and cardiovascular outcome in non-dialysis chronic kidney disease","volume":"107","author":"Emrich","year":"2018","journal-title":"Clin. Res. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"642","DOI":"10.2215\/CJN.08530815","article-title":"Masked hypertension and elevated nighttime blood pressure in CKD: Prevalence and association with target organ damage","volume":"11","author":"Drawz","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.atherosclerosis.2012.03.039","article-title":"Ambulatory arterial stiffness index: A systematic review and meta-analysis","volume":"224","author":"Kollias","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"K\/DOQI Workgroup (2005). K\/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients. Am. J. Kidney Dis., 45, S1\u2013S153.","DOI":"10.1053\/j.ajkd.2005.01.019"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"355","DOI":"10.4103\/0971-4065.148305","article-title":"Role of 24-h ambulatory blood pressure monitoring in children with chronic kidney disease","volume":"25","author":"Gupta","year":"2015","journal-title":"Indian, J. Nephrol."},{"key":"ref_37","unstructured":"National High Blood Pressure Education Program (2019, September 01). The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents, Available online: https:\/\/www.nhlbi.nih.gov \u203a docs \u203a resources \u203a heart \u203a hbp_ped."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1097\/00004872-200210000-00019","article-title":"Distribution of 24-h ambulatory blood pressure in children: Normalized reference values and role of body dimensions","volume":"20","author":"Wuhl","year":"2002","journal-title":"J. Hypertens."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e20171904","DOI":"10.1542\/peds.2017-1904","article-title":"Clinical practice guideline for screening and management of high blood pressure in children and adolescents","volume":"140","author":"Flynn","year":"2017","journal-title":"Pediatrics"},{"key":"ref_40","first-page":"1","article-title":"KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease","volume":"3","author":"Levin","year":"2013","journal-title":"Kidney Int. Suppl."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1681\/ASN.2008030287","article-title":"New equations to estimate GFR in children with CKD","volume":"20","author":"Schwartz","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3843","DOI":"10.1093\/ndt\/gfr655","article-title":"Novel perspectives for investigating congenital anomalies of the kidney and urinary tract (CAKUT)","volume":"26","author":"Renkema","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/S0002-9149(99)80200-8","article-title":"Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease","volume":"76","author":"Daniels","year":"1995","journal-title":"Am. J. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1253\/circj.CJ-15-0412","article-title":"Homocysteine and arginine-to-asymmetric dimethylarginine ratio associated with blood pressure abnormalities in children with early chronic kidney disease","volume":"79","author":"Chien","year":"2015","journal-title":"Circ. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:29:11Z","timestamp":1760189351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/21\/5301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,24]]},"references-count":44,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["ijms20215301"],"URL":"https:\/\/doi.org\/10.3390\/ijms20215301","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,24]]}}}