{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T01:31:42Z","timestamp":1793496702547,"version":"4.5.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Serum levels of amino acids related to urea cycle are associated with risk of type 2 diabetes mellitus (T2DM). Our study aimed to explore whether serum levels of amino acids related to urea cycle, i.e., arginine, citrulline, and ornithine, are also associated with increased risk of chronic kidney disease (CKD) in T2DM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We extracted medical records of 1032 consecutive patients with T2DM from the Electronic Administrative System of Liaoning Medical University First Affiliated Hospital (LMUFAH) system from May 2015 to August 2016. Of them, 855 patients with completed data available were used in the analysis. CKD was defined as estimated glomerular filtration rate (eGFR) &amp;lt;60 mL\/min\/1.73 m<jats:sup>2<\/jats:sup>. Serum amino acids were measured by mass spectrometry (MS) technology. Binary logistic regression was performed to obtain odds ratios (ORs) and their 95% confidence intervals (CIs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>52.3% of the 855 T2DM patients were male, and 143 had CKD. In univariable analysis, high serum citrulline, high ratio of arginine to ornithine, and low ratio of ornithine to citrulline were associated with markedly increased risk of CKD (OR of top vs. bottom tertile: 2.87, 95%CI, 1.79-4.62 &amp;amp; 1.98, 95%CI,1.25-3.14 &amp;amp; 2.56, 95%CI, 1.61-4.07, respectively). In multivariable analysis, the ORs of citrulline and ornithine\/citrulline ratio for CKD remained significant (OR of top vs. bottom tertile: 2.22, 95%CI, 1.29-3.82 &amp;amp; 2.24, 1.29-3.87, respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In Chinese patients with T2DM, high citrulline and low ornithine\/citrulline ratio were associated with increased risk of CKD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1117308","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T06:36:53Z","timestamp":1677739013000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Associations of serum amino acids related to urea cycle with risk of chronic kidney disease in Chinese with type 2 diabetes"],"prefix":"10.3389","volume":"14","author":[{"given":"Wei","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jikun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ninghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong-Ze","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/nrneph.2015.173","article-title":"Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease","volume":"12","author":"Thomas","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-0248","article-title":"Glomerular filtration rate, cardiorenal end points, and all-cause mortality in type 2 diabetic patients","volume":"29","author":"So","year":"2006","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"15018","DOI":"10.1038\/nrdp.2015.18","article-title":"Diabetic kidney disease","volume":"1","author":"Thomas","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.08.026","article-title":"Progression of diabetic kidney disease and trajectory of kidney function decline in Chinese patients with type 2 diabetes","volume":"95","author":"Jiang","year":"2019","journal-title":"Kidney Int"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2011.861","article-title":"Temporal trends in the prevalence of diabetic kidney disease in the united states","volume":"305","author":"de Boer","year":"2011","journal-title":"Jama"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2008.02.024","article-title":"Chronic kidney disease, prevalence of premature cardiovascular disease, and relationship to short-term mortality","volume":"156","author":"McCullough","year":"2008","journal-title":"Am Heart J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.14745","article-title":"Chronic kidney disease diagnosis and management: A review","volume":"322","author":"Chen","year":"2019","journal-title":"Jama"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(12)60033-6","article-title":"Prevalence of chronic kidney disease in China: a cross-sectional survey","volume":"379","author":"Zhang","year":"2012","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1189","article-title":"Targeted metabolomics finds its mark in diabetes research","volume":"62","author":"Bain","year":"2013","journal-title":"Diabetes"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0495","article-title":"Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach","volume":"62","author":"Floegel","year":"2013","journal-title":"Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2307","article-title":"Metabolite profiles and the risk of developing diabetes","volume":"17","author":"Wang","year":"2011","journal-title":"Nat Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.765873","article-title":"Metabolomic profiling of amino acids in human plasma distinguishes diabetic kidney disease from type 2 diabetes mellitus","volume":"8","author":"Zhou","year":"2021","journal-title":"Front Med"},{"key":"B13","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1186\/s12916-017-0974-6","article-title":"Comprehensive metabolic profiling of chronic low-grade inflammation among generally healthy individuals","volume":"15","author":"Pietzner","year":"2017","journal-title":"BMC Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-173377","article-title":"Carbamylated low-density lipoprotein induces oxidative stress and accelerated senescence in human endothelial progenitor cells","volume":"25","author":"Carracedo","year":"2011","journal-title":"FASEB J Off Publ Fed Am Societies Exp Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1210\/me.2009-0152","article-title":"Early hepatic insulin resistance in mice: a metabolomics analysis","volume":"24","author":"Li","year":"2010","journal-title":"Mol Endocrinol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4172\/jpb.S14-001","article-title":"Metabolomic Profiling of Arginine Metabolome Links Altered Methylation to Chronic Kidney Disease Accelerated Atherosclerosis","author":"Mathew","year":"2015","journal-title":"J Proteom Bioinform"},{"key":"B17","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.jprot.2018.09.020","article-title":"Proteomic and metabolomic approaches in the search for biomarkers in chronic kidney disease","volume":"193","author":"Ca\u00f1adas-Garre","year":"2019","journal-title":"J Proteomics"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2012101006","article-title":"A combined epidemiologic and metabolomic approach improves CKD prediction","volume":"24","author":"Rhee","year":"2013","journal-title":"J Am Soc Nephrol: JASN"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12898","article-title":"Plasma tyrosine and its interaction with low high-density lipoprotein cholesterol and the risk of type 2 diabetes mellitus in Chinese","volume":"10","author":"Li","year":"2019","journal-title":"J Diabetes Invest"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1096-9136(199807)15:7<539::Aid-dia668>3.0.Co;2-s","article-title":"Definition, diagnosis and classification of diabetes mellitus and its complications. part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation","volume":"15","author":"Alberti","year":"1998","journal-title":"Diabetic Med J Br Diabetic Assoc"},{"key":"B21","unstructured":"Criteria of weight for adults2013"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2009.549","article-title":"Development and validation of equations estimating glomerular filtration rates in Chinese patients with type 2 diabetes","volume":"77","author":"Leung","year":"2010","journal-title":"Kidney Int"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.00365.x","article-title":"Definition and classification of chronic kidney disease: a position statement from kidney disease: Improving global outcomes (KDIGO)","volume":"67","author":"Levey","year":"2005","journal-title":"Kidney Int"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2147\/ott.S95862","article-title":"A dried blood spot mass spectrometry metabolomic approach for rapid breast cancer detection","volume":"9","author":"Wang","year":"2016","journal-title":"OncoTarg Ther"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.6634","article-title":"Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality","volume":"311","author":"Coresh","year":"2014","journal-title":"Jama"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1053\/j.ackd.2014.03.009","article-title":"Epidemiology and risk factors for diabetic kidney disease","volume":"21","author":"Harjutsalo","year":"2014","journal-title":"Adv chronic Kidney Dis"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.01.024","article-title":"Interplay between lipids and branched-chain amino acids in development of insulin resistance","volume":"15","author":"Newgard","year":"2012","journal-title":"Cell Metab"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1038\/s41467-019-09329-0","article-title":"Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan","volume":"10","author":"Chen","year":"2019","journal-title":"Nat Commun"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002017","article-title":"Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study","volume":"71","author":"Yamagata","year":"2007","journal-title":"Kidney Int"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2013.05.045","article-title":"Obesity and diabetes related plasma amino acid alterations","volume":"46","author":"Zhou","year":"2013","journal-title":"Clin Biochem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1333","article-title":"Small intestinal alterations in severely obese hyperglycemic subjects","volume":"96","author":"Verdam","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063950","article-title":"Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome","volume":"8","author":"Sailer","year":"2013","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2013020126","article-title":"Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease","volume":"24","author":"Sharma","year":"2013","journal-title":"J Am Soc Nephrol JASN"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines8070222","article-title":"mino Acid Metabolites Associated with Chronic Kidney Disease: An Eight-Year Follow-Up Korean Epidemiology Study","volume":"8","author":"Lee","year":"2020","journal-title":"Biomedicines"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2215\/cjn.05540512","article-title":"Plasma metabolomic profiles in different stages of CKD","volume":"8","author":"Shah","year":"2013","journal-title":"Clin J Am Soc Nephrol CJASN"},{"key":"B36","doi-asserted-by":"publisher","first-page":"37","DOI":"10.2215\/cjn.06000613","article-title":"Plasma and urinary amino acid metabolomic profiling in patients with different levels of kidney function","volume":"9","author":"Duranton","year":"2014","journal-title":"Clin J Am Soc Nephrol CJASN"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4102\/ajlm.v10i1.1398","article-title":"Relationship between amino acid ratios and decline in estimated glomerular filtration rate in diabetic and non-diabetic patients in south Africa","volume":"10","author":"Mbhele","year":"2021","journal-title":"Afr J Lab Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1177\/1479164116643916","article-title":"Amino acid metabolism reflecting arginase activity is increased in patients with type 2 diabetes and associated with endothelial dysfunction","volume":"13","author":"K\u00f6vamees","year":"2016","journal-title":"Diabetes Vasc Dis Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00252.2005","article-title":"Route of administration (enteral or parenteral) affects the contribution of l-glutamine to de novo l-arginine synthesis in mice: a stable-isotope study","volume":"291","author":"Boelens","year":"2006","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00026.2005","article-title":"Intestinal renal metabolism of l-citrulline and l-arginine following enteral or parenteral infusion of l-alanyl-L-[2,15N]glutamine or l-[2,15N]glutamine in mice","volume":"289","author":"Boelens","year":"2005","journal-title":"Am J Physiol Gastrointest liver Physiol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00284.2012","article-title":"Arginine de novo and nitric oxide production in disease states","volume":"303","author":"Luiking","year":"2012","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1097\/MNH.0b013e328314b6ca","article-title":"Asymmetric dimethylarginine: a novel marker of risk and a potential target for therapy in chronic kidney disease","volume":"17","author":"Kielstein","year":"2008","journal-title":"Curr Opin Nephrol hypertension"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2011.31","article-title":"The role of asymmetric and symmetric dimethylarginines in renal disease","volume":"7","author":"Schwedhelm","year":"2011","journal-title":"Nat Rev Nephrol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1002\/path.2769","article-title":"Asymmetric dimethylarginine (ADMA) induces chronic kidney disease through a mechanism involving collagen and TGF-\u03b21 synthesis","volume":"223","author":"Mihout","year":"2011","journal-title":"J Pathol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0009-8981(03)00338-3","article-title":"Serum concentrations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in patients with chronic kidney diseases","volume":"336","author":"Fleck","year":"2003","journal-title":"Clinica chimica acta; Int J Clin Chem"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1681\/asn.V131170","article-title":"Marked increase of asymmetric dimethylarginine in patients with incipient primary chronic renal disease","volume":"13","author":"Kielstein","year":"2002","journal-title":"J Am Soc Nephrol JASN"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfl423","article-title":"Steroid pulse therapy impaired endothelial function while increasing plasma high molecule adiponectin concentration in patients with IgA nephropathy","volume":"21","author":"Uchida","year":"2006","journal-title":"Nephrol dialysis Transplant Off Publ Eur Dialysis Transplant Assoc - Eur Renal Assoc"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0096955","article-title":"Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease","volume":"9","author":"Nkuipou-Kenfack","year":"2014","journal-title":"PLoS One"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2014111063","article-title":"Serum trimethylamine-N-Oxide is elevated in CKD and correlates with coronary atherosclerosis burden","volume":"27","author":"Stubbs","year":"2016","journal-title":"J Am Soc Nephrol JASN"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2005010076","article-title":"Asymmetrical dimethylarginine predicts progression to dialysis and death in patients with chronic kidney disease: a competing risks modeling approach","volume":"16","author":"Ravani","year":"2005","journal-title":"J Am Soc Nephrol JASN"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2005020179","article-title":"Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study","volume":"16","author":"Fliser","year":"2005","journal-title":"J Am Soc Nephrol JASN"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1177\/2050640617737632","article-title":"Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis","volume":"6","author":"Fragkos","year":"2018","journal-title":"United Eur Gastroenterol J"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1117308\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T06:36:58Z","timestamp":1677739018000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1117308\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,2]]},"references-count":52,"alternative-id":["10.3389\/fendo.2023.1117308"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1117308","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,2]]},"article-number":"1117308"}}