{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T19:55:58Z","timestamp":1787169358527,"version":"build-2736575974"},"reference-count":40,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Renal care research and health promotion association","award":["CGH-MR-A11426"],"award-info":[{"award-number":["CGH-MR-A11426"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic inter-dialytic volume overload and uremic inflammation activate TGF-\u03b2\/Smad3 and p38 MAPK pathways, inducing connective tissue growth factors (CCN2\/CTGF)-mediated fibrosis and NT-proBNP secretion from over-stretched cardiomyocytes. The combined rise in CTGF and NT-proBNP reflects myocardial fibrosis, stiffness and remodeling, predicting cardiovascular (CV) death in maintenance hemodialysis (MHD) patients. From molecular pathology to clinical translation, circulating CCN2\/CTGF and NT-proBNP levels and bio-clinical data among MHD patients were measured in this prospective cohort. Multivariate Cox regression analysis identified independent predictors of mortality, which were incorporated into a composite risk-score model. The predictive performance for all-cause, CV, and sudden cardiac death (SCD) was assessed using receiver operating characteristic (ROC) survival analysis. CCN2\/CTGF, NT-proBNP, age, serum albumin, MHD vintage, high-sensitivity C-reactive protein, smoking, and diabetes mellitus were significant predictors. The integrated model yielded areas under the curve of 0.91 for all-cause mortality, 0.88 for CV mortality, and 0.87 for SCD. Integrated complementary biomarkers and clinical parameters significantly improve mortality risk prediction in MHD patients. This synergistic model provides clinicians with a robust tool for early CV screening, individualized intervention, and precision management for high-risk populations.<\/jats:p>","DOI":"10.3390\/ijms262311350","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T14:59:04Z","timestamp":1763996344000},"page":"11350","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CCN2\/CTGF-Driven Myocardial Fibrosis and NT-proBNP Synergy as Predictors of Mortality in Maintenance Hemodialysis"],"prefix":"10.3390","volume":"26","author":[{"given":"Wen-Chin","family":"Ko","sequence":"first","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei City 242062, Taiwan"},{"name":"Division of Cardiac Electrophysiology, Department of Cardiovascular Center, Cathay General Hospital, Taipei 106438, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che-Shao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Public Health, Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei 106319, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Healthcare Information and Management, Ming Chuan University, Taoyuan Campus, Taoyuan 333321, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Taipei Veterans General Hospital, Taoyuan Branch, Taoyuan 330023, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Sheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Renal Care Research and Health Promotion Association, New Taipei City 220050, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hung-Chi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300102, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9903-7473","authenticated-orcid":false,"given":"Jia-Feng","family":"Chang","sequence":"additional","affiliation":[{"name":"Renal Care Research and Health Promotion Association, New Taipei City 220050, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Yuanpei University of Medical Technology, Hsinchu 300102, Taiwan"},{"name":"Department of Nursing, Yuanpei University of Medical Technology, Hsinchu 300102, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1161\/CIRCULATIONAHA.108.807362","article-title":"Fluid Retention Is Associated with Cardiovascular Mortality in Patients Undergoing Long-Term Hemodialysis","volume":"119","author":"Regidor","year":"2009","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1093\/eurheartj\/ehx584","article-title":"A biomarker-based risk score to predict death in patients with atrial fibrillation: The ABC (age, biomarkers, clinical history) death risk score","volume":"39","author":"Hijazi","year":"2017","journal-title":"Eur. Hear. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.kint.2021.09.013","article-title":"Management of Fluid Overload in Hemodialysis Patients","volume":"100","author":"Lopez","year":"2021","journal-title":"Kidney Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"pi123","DOI":"10.1093\/qjmed\/hcaa052.020","article-title":"Interdialytic Weight Gain and Its Relation to Outcome among Patients on Maintenance Hemodialysis","volume":"113","author":"Ibrahim","year":"2020","journal-title":"QJM Int. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chang, J.F., Wu, C.C., Hsieh, C.Y., Li, Y.Y., Wang, T.M., and Liou, J.C. (2020). A Joint Evaluation of Impaired Cardiac Sympathetic Responses and Malnutrition-Inflammation Cachexia for Mortality Risks in Hemodialysis Patients. Front. Med., 27.","DOI":"10.3389\/fmed.2020.00099"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mitsas, A.C., Elzawawi, M., Mavrogeni, S., Boekels, M., Khan, A., Eldawy, M., Stamatakis, I., Kouris, D., Daboul, B., and Gunkel, O. (2022). Heart Failure and Cardiorenal Syndrome: A Narrative Review on Pathophysiology, Diagnostic and Therapeutic Regimens\u2014From a Cardiologist\u2019s View. J. Clin. Med., 11.","DOI":"10.3390\/jcm11237041"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1016\/j.ekir.2022.07.165","article-title":"Predicting Kidney Failure, Cardiovascular Disease and Death in Advanced CKD Patients","volume":"7","author":"Chava","year":"2022","journal-title":"Kidney Int. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"840","DOI":"10.2337\/dc17-2083","article-title":"Plasma Connective Tissue Growth Factor (CTGF\/CCN2) Levels Predict Myocardial Infarction in the Veterans Affairs Diabetes Trial (VADT) Cohort","volume":"41","author":"Hunt","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Chen, Y.-H., Fu, Y.-C., and Wu, M.-J. (2019). NT-ProBNP Predicts Total Mortality, Emergency Department Visits, Hospitalization, Intensive-Care Unit Admission, and Cardiovascular Events in Hemodialysis Patients. J. Clin. Med., 8.","DOI":"10.3390\/jcm8020238"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Chen, Z., Zhang, N., Chu, H.Y., Yu, Y., Zhang, Z.-K., Zhang, G., and Zhang, B.-T. (2020). Connective Tissue Growth Factor: From Molecular Understandings to Drug Discovery. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.593269"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ren, M., Yao, S., Chen, T., Luo, H., Tao, X., Jiang, H., Yang, X., Zhang, H., Yu, S., and Wang, Y. (2024). Connective Tissue Growth Factor: Regulation, Diseases, and Drug Discovery. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094692"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.jacbts.2018.10.007","article-title":"Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction","volume":"4","author":"Vainio","year":"2019","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Watanabe, K., Sato, E., Mishima, E., Miyazaki, M., and Tanaka, T. (2023). What\u2019s New in the Molecular Mechanisms of Diabetic Kidney Disease: Recent Advances. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010570"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00392-013-0626-6","article-title":"Connective tissue growth factor (CTGF\/CCN2): Diagnostic and prognostic value in acute heart failure","volume":"103","author":"Behnes","year":"2013","journal-title":"Clin. Res. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hoedt, C.H.D., van Gelder, M.K., Grooteman, M.P., Nub\u00e9, M.J., Blankestijn, P.J., Goldschmeding, R., Kok, R.J., Bots, M.L., Dorpel, M.A.v.D., and Gerritsen, K.G.F. (2019). Connective Tissue Growth Factor Is Related to All-cause Mortality in Hemodialysis Patients and Is Lowered by On-line Hemodiafiltration: Results from the Convective Transport Study. Toxins, 11.","DOI":"10.3390\/toxins11050268"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gallo, G., Lanza, O., and Savoia, C. (2023). New Insight in Cardiorenal Syndrome: From Biomarkers to Therapy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24065089"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Goffredo, G., Barone, R., Di Terlizzi, V., Correale, M., Brunetti, N.D., and Iacoviello, M. (2021). Biomarkers in cardiorenal syndrome. J. Clin. Med., 10.","DOI":"10.3390\/jcm10153433"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cao, Z., Jia, Y., and Zhu, B. (2019). BNP and NT-proBNP as Diagnostic Biomarkers for Cardiac Dysfunction in Both Clinical and Forensic Medicine. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081820"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e078063","DOI":"10.1136\/bmj-2023-078063","article-title":"Predicting the risks of kidney failure and death in adults with moderate to severe chronic kidney disease: Multinational, longitudinal, population based, cohort study","volume":"385","author":"Liu","year":"2024","journal-title":"BMJ"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chang, J.F., Chen, P.C., Hsieh, C.Y., and Liou, J.C. (2021). A Growth Differentiation Factor 15-Based Risk Score Model to Predict Mortality in Hemodialysis Patients. Diagnostics, 11.","DOI":"10.3390\/diagnostics11020286"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41591-018-0239-8","article-title":"Predicting the early risk of chronic kidney disease in patients with diabetes using real-world data","volume":"25","author":"Ravizza","year":"2019","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1161\/CIRCRESAHA.110.217737","article-title":"Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation","volume":"106","author":"Leask","year":"2010","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3056","DOI":"10.3748\/wjg.v13.i22.3056","article-title":"Transforming growth factor-\u03b2 and fibrosis","volume":"13","author":"Verrecchia","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5635","DOI":"10.1091\/mbc.e04-06-0490","article-title":"CCN2 (Connective Tissue Growth Factor) Promotes Fibroblast Adhesion to Fibronectin","volume":"15","author":"Chen","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1165\/rcmb.2009-0068OC","article-title":"Conditional Overexpression of Connective Tissue Growth Factor Disrupts Postnatal Lung Development","volume":"42","author":"Wu","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1172\/JCI7362","article-title":"Mechanical strain activates BNP gene transcription through a p38\/NF-\u03baB\u2013dependent mechanism","volume":"104","author":"Liang","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1161\/01.RES.71.1.9","article-title":"Expression of A-, B-, and C-type natriuretic peptide genes in failing and developing human ventricles. Correlation with expression of the Ca(2+)-ATPase gene","volume":"71","author":"Takahashi","year":"1992","journal-title":"Circ. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1161\/01.HYP.0000254415.31362.a7","article-title":"Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling","volume":"49","author":"Takimoto","year":"2007","journal-title":"Hypertension"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/eurheartj\/ehn600","article-title":"Growth differentiation factor-15 as a prognostic marker in patients with acute myocardial infarction","volume":"30","author":"Khan","year":"2009","journal-title":"Eur. Heart J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1338","DOI":"10.1016\/j.amjmed.2025.04.024","article-title":"Cardiac Biomarkers for the Prediction, Discrimination, and Risk-Stratification of Type 2 Myocardial Infarction: A Critical Appraisal","volume":"138","author":"Pollmann","year":"2025","journal-title":"Am. J. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.4174\/astr.2022.102.3.147","article-title":"External validation of risk prediction platforms for pancreatic fistula after pancreatoduodenectomy using nomograms and artificial intelligence","volume":"102","author":"Yoon","year":"2022","journal-title":"Ann. Surg. Treat. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.amjmed.2024.04.002","article-title":"Multimodal Machine Learning for Prediction of 30-Day Readmission Risk in Elderly Population","volume":"137","author":"Loutati","year":"2024","journal-title":"Am. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Xu, L., Liu, J., Han, C., and Ai, Z. (2022). The Application of Machine Learning in Predicting Mortality Risk in Patients with Severe Femoral Neck Fractures: Prediction Model Development Study. JMIR Bioinform. Biotechnol., 3.","DOI":"10.2196\/38226"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/ejhf.3059","article-title":"A machine learning-derived risk score predicts mortality in East Asian patients with acute heart failure","volume":"25","author":"Park","year":"2023","journal-title":"Eur. J. Heart Fail."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1096\/fj.03-1273rev","article-title":"TGF\u2014\u03b2 signaling and the fibrotic response","volume":"18","author":"Leask","year":"2004","journal-title":"FASEB J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1093\/cvr\/cvq181","article-title":"Trimetazidine inhibits pressure overload-induced cardiac fibrosis through NADPH oxidase\u2013ROS\u2013CTGF pathway","volume":"88","author":"Liu","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41580-019-0108-4","article-title":"Identification of bioactive metabolites using activity metabolomics","volume":"20","author":"Rinschen","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ko, W.-C., Choy, C.-S., Lin, W.-N., Chang, S.-W., Liou, J.-C., Tung, T.-H., Hsieh, C.-Y., and Chang, J.-F. (2018). Galectin-3 Interacts with Vascular Cell Adhesion Molecule-1 to Increase Cardiovascular Mortality in Hemodialysis Patients. J. Clin. Med., 7.","DOI":"10.3390\/jcm7100300"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1038\/s41591-022-01978-x","article-title":"Health effects associated with smoking: A Burden of Proof study","volume":"28","author":"Dai","year":"2022","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5081","DOI":"10.1002\/ehf2.13576","article-title":"NT-proBNP\/BNP ratio for prognostication in European Caucasian patients enrolled in a heart failure prevention programme","volume":"8","author":"Sweeney","year":"2021","journal-title":"ESC Heart Fail."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11350\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T14:59:12Z","timestamp":1763996352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11350"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":40,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311350"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311350","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]}}}