{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:15:57Z","timestamp":1785849357602,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Faculty of Medicine and Health at \u00d6rebro University"},{"name":"Swedish Knowledge Foundation"},{"name":"European Renal Association"},{"DOI":"10.13039\/501100007308","name":"Swedish Medical Association","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007308","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Trimethylamine-N-oxide (TMAO), a gut microbiota-derived dietary metabolite, is linked to progression of chronic kidney disease (CKD). Megalin, a renal proximal tubule receptor crucial for albumin reabsorption, also plays a role in CKD. However, the relationship between them is not well explored. The aim of this study was to investigate if there are any correlations between the levels of TMAO, megalin, lysine and markers of tubular damage in CKD. Urinary metabolites (TMAO, choline, L-carnitine, betaine, lysine) and tubular markers (megalin, albumin, EGF, MCP-1) were quantified by LC-MS\/MS and ELISA. Associations were evaluated using analysis of covariance (ANCOVA) adjusted for age and diabetes, with false discovery rate correction. Compared with controls, CKD patients showed higher urinary choline (FDR &lt; 0.001), betaine (FDR = 0.007), lysine (FDR = 0.005), and soluble megalin (FDR &lt; 0.001) but lower EGF and EGF\/MCP-1 ratio (both FDR &lt; 0.001). Correlation analyses revealed that serum TMAO was positively associated with soluble megalin and negatively with EGF\/MCP-1 ratio. Choline, L-carnitine, and betaine were positively correlated with megalin. This cross-sectional study identifies associations between urinary metabolites, megalin, and tubular injury markers in advanced CKD. Although causality cannot be inferred, the results point to a potential metabolic\u2013tubular link that should be explored in future longitudinal and mechanistic studies.<\/jats:p>","DOI":"10.3390\/toxins17120592","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T08:39:18Z","timestamp":1765442358000},"page":"592","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Correlations Between Trimethylamine-N-Oxide, Megalin, Lysine and Markers of Tubular Damage in Chronic Kidney Disease"],"prefix":"10.3390","volume":"17","author":[{"given":"Stefania","family":"Kapetanaki","sequence":"first","affiliation":[{"name":"School of Medical Sciences, \u00d6rebro University, Campus US\u00d6, 701 82 \u00d6rebro, Sweden"},{"name":"Nephrology Department, Karolinska University Hospital, 141 86 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samira","family":"Salihovic","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, \u00d6rebro University, Campus US\u00d6, 701 82 \u00d6rebro, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2244-9816","authenticated-orcid":false,"given":"Ashok Kumar","family":"Kumawat","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, \u00d6rebro University, Campus US\u00d6, 701 82 \u00d6rebro, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad A.","family":"Massy","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Ambroise Par\u00e9 University Hospital, APHP, Boulogne-Billancourt, F-92100 Paris, France"},{"name":"Inserm Unit 1018, Team 5, CESP, H\u00f4pital Paul Brousse, Paris-Saclay University (UPS), Versailles Saint-Quentin-en-Yvelines University (UVSQ), F-94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2517-034X","authenticated-orcid":false,"given":"Katarina","family":"Persson","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, \u00d6rebro University, Campus US\u00d6, 701 82 \u00d6rebro, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6501-8293","authenticated-orcid":false,"given":"Peter","family":"Barany","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8785-4820","authenticated-orcid":false,"given":"Peter","family":"Stenvinkel","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Clinical Science, Intervention and Technology, Division of Renal Medicine, Karolinska Institutet, 141 52 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isak","family":"Demirel","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, \u00d6rebro University, Campus US\u00d6, 701 82 \u00d6rebro, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s12325-021-01927-z","article-title":"A Narrative Review of Chronic Kidney Disease in Clinical Practice: Current Challenges and Future Perspectives","volume":"39","author":"Evans","year":"2022","journal-title":"Adv. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hill, N.R., Fatoba, S.T., Oke, J.L., Hirst, J.A., O\u2019Callaghan, C.A., Lasserson, D.S., and Hobbs, F.D.R. (2016). Global Prevalence of Chronic Kidney Disease\u2014A Systematic Review and Meta-Analysis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158765"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/CIRCRESAHA.116.305360","article-title":"Gut Microbiota-Dependent Trimethylamine-Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease","volume":"116","author":"Tang","year":"2015","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Velasquez, M.T., Ramezani, A., Manal, A., and Raj, D.S. (2016). Trimethylamine-Oxide: The Good, the Bad and the Unknown. Toxins, 8.","DOI":"10.3390\/toxins8110326"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Miao, L.N., Du, J.P., Chen, Z.H., Shi, D.Z., and Qu, H. (2021). Effects of Microbiota-Driven Therapy on Circulating Trimethylamine-N-Oxide Metabolism: A Systematic Review and Meta-Analysis. Front. Cardiovasc. Med., 8.","DOI":"10.3389\/fcvm.2021.710567"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1042\/CS20171107","article-title":"Altered microbiome in chronic kidney disease: Systemic effects of gut-derived uremic toxins","volume":"132","author":"Lau","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pelletier, C.C., Croyal, M., Ene, L., Aguesse, A., Billon-Crossouard, S., Krempf, M., Lemoine, S., Guebre-Egziabher, F., Juillard, L., and Soulage, C.O. (2019). Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate. Toxins, 11.","DOI":"10.3390\/toxins11110635"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13781","DOI":"10.1038\/s41598-017-13739-9","article-title":"TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function","volume":"7","author":"Gruppen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.kint.2016.01.014","article-title":"Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events","volume":"89","author":"Kim","year":"2016","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.kint.2017.03.053","article-title":"The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease","volume":"92","author":"Tomlinson","year":"2017","journal-title":"Kidney Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1681\/ASN.2014111063","article-title":"Serum Trimethylamine--Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden","volume":"27","author":"Stubbs","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1681\/ASN.20233411S1664b","article-title":"Associations of Plasma Trimethylamine N-Oxide-Related Metabolites with the Development and Progression of Albuminuria","volume":"34","author":"Wang","year":"2023","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1681\/ASN.0000000000000344","article-title":"The Gut Microbial Metabolite Trimethylamine N -oxide, Incident CKD, and Kidney Function Decline","volume":"35","author":"Wang","year":"2024","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00467-011-1992-9","article-title":"Tubulointerstitial injury and the progression of chronic kidney disease","volume":"27","author":"Hodgkins","year":"2012","journal-title":"Pediatr. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.2337\/dc11-1684","article-title":"Significance of Urinary Full-Length and Ectodomain Forms of Megalin in Patients with Type 2 Diabetes","volume":"35","author":"Ogasawara","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s10557-020-07035-4","article-title":"The Potential of Albuminuria as a Biomarker of Diabetic Complications","volume":"35","author":"Raja","year":"2021","journal-title":"Cardiovasc. Drug Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.kint.2015.11.007","article-title":"Megalin and cubilin in proximal tubule protein reabsorption: From experimental models to human disease","volume":"89","author":"Nielsen","year":"2016","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1681\/ASN.2008111212","article-title":"The Case for Using Albuminuria in Staging Chronic Kidney Disease","volume":"20","author":"Gansevoort","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"109810","DOI":"10.1016\/j.diabres.2022.109810","article-title":"Urinary C-megalin as a novel biomarker of progression to microalbuminuria: A cohort study based on the diabetes Distress and Care Registry at Tenri (DDCRT 22)","volume":"186","author":"Nishiwaki","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kapetanaki, S., Kumawat, A.K., Persson, K., and Demirel, I. (2022). TMAO Suppresses Megalin Expression and Albumin Uptake in Human Proximal Tubular Cells Via PI3K and ERK Signaling. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23168856"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1161\/HYPERTENSIONAHA.119.12873","article-title":"Urinary Renin in Patients and Mice With Diabetic Kidney Disease","volume":"74","author":"Tang","year":"2019","journal-title":"Hypertension"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1161\/HYPERTENSIONAHA.120.14845","article-title":"Megalin A Novel Endocytic Receptor for Prorenin and Renin","volume":"75","author":"Sun","year":"2020","journal-title":"Hypertension"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/sj.ki.5000272","article-title":"Characterization of proteinuria and tubular protein uptake in a new model of oral L-lysine administration in rats","volume":"69","author":"Thelle","year":"2006","journal-title":"Kidney Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4099","DOI":"10.1038\/s41467-022-31670-0","article-title":"Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension","volume":"13","author":"Rinschen","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1093\/ajcn\/nqac278","article-title":"The association between TMAO, CMPF, and clinical outcomes in advanced chronic kidney disease: Results from the European QUALity (EQUAL) Study","volume":"116","author":"Dai","year":"2022","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.34067\/KID.0000000000000158","article-title":"Urinary Metabolite Profile Predicting the Progression of CKD","volume":"4","author":"Kim","year":"2023","journal-title":"Kidney360"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kapetanaki, S., Kumawat, A.K., Persson, K., and Demirel, I. (2021). The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK\/Akt\/mTOR Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111864"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9070","DOI":"10.1038\/s41598-024-58084-w","article-title":"TMAO enhances TNF-alpha mediated fibrosis and release of inflammatory mediators from renal fibroblasts","volume":"14","author":"Stefania","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Missailidis, C., Hallqvist, J., Qureshi, A.R., Barany, P., Heimburger, O., Lindholm, B., Stenvinkel, P., and Bergman, P. (2016). Serum Trimethylamine--Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0141738"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/sj.ki.5002585","article-title":"A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease","volume":"73","author":"Fouque","year":"2008","journal-title":"Kidney Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108312","DOI":"10.1016\/j.jdiacomp.2022.108312","article-title":"Urinary A- and C-megalin predict progression of diabetic kidney disease: An exploratory retrospective cohort study","volume":"36","author":"Iida","year":"2022","journal-title":"J. Diabetes Complicat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/ki.2010.169","article-title":"The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo","volume":"78","author":"Christ","year":"2010","journal-title":"Kidney Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.2337\/db16-1031","article-title":"Exocytosis-Mediated Urinary Full-Length Megalin Excretion Is Linked With the Pathogenesis of Diabetic Nephropathy","volume":"66","author":"De","year":"2017","journal-title":"Diabetes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"975","DOI":"10.2337\/dc10-1545","article-title":"Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes","volume":"34","author":"Nauta","year":"2011","journal-title":"Diabetes Care"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.21037\/atm.2016.10.64","article-title":"Epidermal growth factor as a prognostic biomarker in chronic kidney diseases","volume":"4","author":"Isaka","year":"2016","journal-title":"Ann. Transl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Satirapoj, B., Dispan, R., Radinahamed, P., and Kitiyakara, C. (2018). Urinary epidermal growth factor, monocyte chemoattractant protein-1 or their ratio as predictors for rapid loss of renal function in type 2 diabetic patients with diabetic kidney disease. BMC Nephrol., 19.","DOI":"10.1186\/s12882-018-1043-x"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1172\/JCI4876","article-title":"Monocyte chemoattractant protein-1 promotes macrophage-mediated tubular injury, but not glomerular injury, in nephrotoxic serum nephritis","volume":"103","author":"Tesch","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e265","DOI":"10.1515\/cclm-2019-0152","article-title":"Stability of tubular damage markers epidermal growth factor and heparin-binding EGF-like growth factor in urine","volume":"57","author":"Harskamp","year":"2019","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1159\/000519603","article-title":"Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38\/MAPK Signaling and Upregulation of HuR","volume":"47","author":"Lai","year":"2022","journal-title":"Kidney Blood Press. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1016\/j.ekir.2021.01.012","article-title":"Evaluation of Urinary Biomarkers of Proximal Tubular Injury, Inflammation, and Fibrosis in Patients With Albuminuric and Nonalbuminuric Diabetic Kidney Disease","volume":"6","author":"Phanish","year":"2021","journal-title":"Kidney Int. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s13668-022-00426-z","article-title":"The Role of Betaine in Patients With Chronic Kidney Disease: A Narrative Review","volume":"11","author":"Alvarenga","year":"2022","journal-title":"Curr. Nutr. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1093\/ndt\/gfy020","article-title":"Increased urinary osmolyte excretion indicates chronic kidney disease severity and progression rate","volume":"33","author":"Gil","year":"2018","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Liu, J.J., Liu, S., Gurung, R.L., Lee, J., Zheng, H.L., Ang, K., Chan, C., Lee, L.S., Han, S.R., and Kovalik, J.P. (2025). Urine Choline Oxidation Metabolites Predict Chronic Kidney Disease Progression in Patients With Type 2 Diabetes. J. Clin. Endocr. Metab., dgaf281.","DOI":"10.1210\/clinem\/dgaf281"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1007\/BF01721888","article-title":"Serum levels and urine excretion of L-carnitine in patients with normal and impaired kidney function","volume":"62","author":"Leschke","year":"1984","journal-title":"Klin. Wochenschr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"153","DOI":"10.2739\/kurumemedj.MS663001","article-title":"Kinetics of Serum Carnitine Fractions in Patients with Chronic Kidney Disease Not on Dialysis","volume":"66","author":"Yano","year":"2021","journal-title":"Kurume Med. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1161\/ATVBAHA.120.314139","article-title":"Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease","volume":"40","author":"Gupta","year":"2020","journal-title":"Arter. Throm Vas."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/ndt\/gfs277","article-title":"The EQUAL study: A European study in chronic kidney disease stage 4 patients","volume":"27","author":"Jager","year":"2012","journal-title":"Nephrol. Dial. Transpl."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/12\/592\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T05:15:16Z","timestamp":1765602916000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/12\/592"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,11]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["toxins17120592"],"URL":"https:\/\/doi.org\/10.3390\/toxins17120592","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,11]]}}}