{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T09:19:19Z","timestamp":1770283159729,"version":"3.49.0"},"reference-count":119,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,14]],"date-time":"2020-03-14T00:00:00Z","timestamp":1584144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GO1801\/5-1 and SFB\/TRR219 C02"],"award-info":[{"award-number":["GO1801\/5-1 and SFB\/TRR219 C02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the \u2018point of no return\u2019. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.<\/jats:p>","DOI":"10.3390\/toxins12030181","type":"journal-article","created":{"date-parts":[[2020,3,20]],"date-time":"2020-03-20T07:29:07Z","timestamp":1584689347000},"page":"181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Cardiovascular Calcification in Chronic Kidney Disease\u2014Therapeutic Opportunities"],"prefix":"10.3390","volume":"12","author":[{"given":"Anika","family":"Himmelsbach","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, Medical Faculty, RWTH, Aachen University, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carina","family":"Ciliox","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, Medical Faculty, RWTH, Aachen University, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7973-1329","authenticated-orcid":false,"given":"Claudia","family":"Goettsch","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Cardiology, Medical Faculty, RWTH, Aachen University, 52074 Aachen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2459\/JCM.0b013e32834058d1","article-title":"Cardiovascular and noncardiovascular comorbidities in patients with chronic heart failure","volume":"12","author":"Metra","year":"2011","journal-title":"J. Cardiovasc. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1093\/eurheartj\/ehy083","article-title":"The new SFB\/TRR219 Research Centre","volume":"39","author":"Noels","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"665","DOI":"10.3390\/toxins6020665","article-title":"Protein-bound uremic toxins: New culprits of cardiovascular events in chronic kidney disease patients","volume":"6","author":"Ito","year":"2014","journal-title":"Toxins"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1161\/CIRCRESAHA.112.278457","article-title":"Cardiorenal syndrome: The emerging role of protein-bound uremic toxins","volume":"111","author":"Lekawanvijit","year":"2012","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.2215\/CJN.03980609","article-title":"Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients","volume":"4","author":"Barreto","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1093\/ndt\/gfv111","article-title":"Vascular calcification in chronic kidney disease: An update","volume":"31","author":"Schlieper","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.18632\/aging.102046","article-title":"The interplay between mineral metabolism, vascular calcification and inflammation in Chronic Kidney Disease (CKD): Challenging old concepts with new facts","volume":"11","author":"Viegas","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"192","DOI":"10.2174\/1573403X14666180619103258","article-title":"Role of Bisphosphonates in Vascular calcification and Bone Metabolism: A Clinical Summary","volume":"14","author":"Dayanand","year":"2018","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/BF02390833","article-title":"Bone loss and the progression of abdominal aortic calcification over a 25 year period: The Framingham Heart Study","volume":"68","author":"Kiel","year":"2001","journal-title":"Calcif. Tissue Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1359\/JBMR.050711","article-title":"Relationship between osteoporosis and cardiovascular disease in postmenopausal women","volume":"20","author":"Tanko","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1053\/j.jrn.2018.05.006","article-title":"Overview of the 2017 KDIGO CKD-MBD Update: Practice Implications for Adult Hemodialysis Patients","volume":"29","author":"Beto","year":"2019","journal-title":"J. Ren. Nutr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s00392-018-1260-0","article-title":"Mechanisms of cardiovascular complications in chronic kidney disease: Research focus of the Transregional Research Consortium SFB TRR219 of the University Hospital Aachen (RWTH) and the Saarland University","volume":"107","author":"Marx","year":"2018","journal-title":"Clin. Res. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1161\/CIRCULATIONAHA.113.003625","article-title":"Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: Implications for statin therapy from the multi-ethnic study of atherosclerosis","volume":"129","author":"Martin","year":"2014","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nmat4519","article-title":"Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques","volume":"15","author":"Hutcheson","year":"2016","journal-title":"Nat. Mater."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1525-139X.2007.00255.x","article-title":"The vascular biology of calcification","volume":"20","author":"Shroff","year":"2007","journal-title":"Semin. Dial."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1093\/ndt\/gfv041","article-title":"The vulnerable patient with chronic kidney disease","volume":"31","author":"Schlieper","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1161\/01.HYP.0000219635.51844.da","article-title":"Calcification and cardiovascular health: New insights into an old phenomenon","volume":"47","author":"Ketteler","year":"2006","journal-title":"Hypertension"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1681\/ASN.2011121191","article-title":"Mechanistic insights into vascular calcification in CKD","volume":"24","author":"Shroff","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1159\/000496532","article-title":"Recent Advances in the Management of Vascular Calcification in Patients with End-Stage Renal Disease","volume":"198","author":"Nitta","year":"2019","journal-title":"Contrib. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ferrer, M.D., Ketteler, M., Tur, F., Tur, E., Isern, B., Salcedo, C., Joubert, P.H., Behets, G.J., Neven, E., and D\u2019Haese, P.C. (2018). Characterization of SNF472 pharmacokinetics and efficacy in uremic and non-uremic rats models of cardiovascular calcification. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0197061"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Raggi, P., Bellasi, A., Bushinsky, D., Bover, J., Rodriguez, M., Ketteler, M., Sinha, S., Salcedo, C., Gillotti, K., and Padgett, C. (2019). Slowing Progression of Cardiovascular Calcification with SNF472 in Patients on Hemodialysis: Results of a Randomized, Phase 2b Study. Circulation.","DOI":"10.1161\/CIRCULATIONAHA.119.044195"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hewitson, T.D., Holt, S.G., and Smith, E.R. (2015). Animal models to study links between cardiovascular disease and renal failure and their relevance to human pathology. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00465"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1093\/ndt\/gft071","article-title":"Animal models of chronic kidney disease: Useful but not perfect","volume":"28","author":"Becker","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1159\/000299794","article-title":"Vascular calcification in animal models of CKD: A review","volume":"31","author":"Shobeiri","year":"2010","journal-title":"Am. J. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3177\/jnsv.28.519","article-title":"Metabolic effects of dietary purine in rats","volume":"28","author":"Yokozawa","year":"1982","journal-title":"J. Nutr. Sci. Vitaminol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1038\/ki.2012.322","article-title":"Vitamin D receptor agonists increase klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet","volume":"82","author":"Lau","year":"2012","journal-title":"Kidney Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1159\/000445171","article-title":"Non-Transgenic Mouse Models of Kidney Disease","volume":"133","author":"Rabe","year":"2016","journal-title":"Nephron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/ki.2009.83","article-title":"Phosphate feeding induces arterial medial calcification in uremic mice: Role of serum phosphorus, fibroblast growth factor-23, and osteopontin","volume":"75","author":"Pai","year":"2009","journal-title":"Kidney Int."},{"key":"ref_29","first-page":"51","article-title":"Implications of gender difference in coronary calcification as assessed by ct coronary angiography","volume":"2014","author":"Makaryus","year":"2014","journal-title":"Clin. Med. Insights Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1093\/ndt\/gfi303","article-title":"In mice, proteinuria and renal inflammatory responses to albumin overload are strain-dependent","volume":"21","author":"Ishola","year":"2006","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1046\/j.1523-1755.2003.00284.x","article-title":"Sevelamer hydrochloride attenuates kidney and cardiovascular calcifications in long-term experimental uremia","volume":"64","author":"Cozzolino","year":"2003","journal-title":"Kidney Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/ki.2013.34","article-title":"Effect of a magnesium-based phosphate binder on medial calcification in a rat model of uremia","volume":"83","author":"Behets","year":"2013","journal-title":"Kidney Int."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Neven, E., De Schutter, T.M., Dams, G., Gundlach, K., Steppan, S., Buchel, J., Passlick-Deetjen, J., D\u2019Haese, P.C., and Behets, G.J. (2014). A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0107067"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1053\/j.ajkd.2016.05.015","article-title":"Phosphate-Binding Agents in Adults With CKD: A Network Meta-analysis of Randomized Trials","volume":"68","author":"Palmer","year":"2016","journal-title":"Am. J. Kidney Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/S0140-6736(13)60897-1","article-title":"Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: An updated systematic review and meta-analysis","volume":"382","author":"Jamal","year":"2013","journal-title":"Lancet"},{"key":"ref_36","first-page":"CD006023","article-title":"Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD)","volume":"8","author":"Ruospo","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1001\/jama.2016.19468","article-title":"Effect of Etelcalcetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism: A Randomized Clinical Trial","volume":"317","author":"Block","year":"2017","journal-title":"JAMA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/aps.2016.83","article-title":"Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition","volume":"37","author":"Wu","year":"2016","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.2147\/DDDT.S134103","article-title":"Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: A review on current data and place in therapy","volume":"12","author":"Friedl","year":"2018","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1056\/NEJMoa1205624","article-title":"Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis","volume":"367","author":"Investigators","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1093\/ndt\/gfq725","article-title":"The ADVANCE study: A randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis","volume":"26","author":"Raggi","year":"2011","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Palmer, S.C., Nistor, I., Craig, J.C., Pellegrini, F., Messa, P., Tonelli, M., Covic, A., and Strippoli, G.F. (2013). Cinacalcet in patients with chronic kidney disease: A cumulative meta-analysis of randomized controlled trials. PLoS Med., 10.","DOI":"10.1371\/journal.pmed.1001436"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1038\/s41598-018-20552-5","article-title":"Cinacalcet use and the risk of cardiovascular events, fractures and mortality in chronic kidney disease patients with secondary hyperparathyroidism","volume":"8","author":"Evans","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Li, M., You, L., Li, H., Ni, L., Gu, Y., Hao, C., and Chen, J. (2012). Effects and safety of calcimimetics in end stage renal disease patients with secondary hyperparathyroidism: A meta-analysis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048070"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"221","DOI":"10.2215\/CJN.02550508","article-title":"Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue","volume":"4","author":"Toussaint","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1038\/ki.2008.356","article-title":"Bisphosphonate nephrotoxicity","volume":"74","author":"Perazella","year":"2008","journal-title":"Kidney Int."},{"key":"ref_47","first-page":"534","article-title":"Differences in nephrotoxicity of intravenous bisphosphonates for the treatment of malignancy-related bone disease","volume":"29","author":"Bergner","year":"2006","journal-title":"Onkologie"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1681\/ASN.V1261164","article-title":"Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate","volume":"12","author":"Markowitz","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Verhulst, A., Sun, S., McKenna, C.E., and D\u2019Haese, P.C. (2015). Endocytotic uptake of zoledronic acid by tubular cells may explain its renal effects in cancer patients receiving high doses of the compound. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121861"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1055\/s-0033-1343776","article-title":"Pathologic fractures in bisphosphonate-related osteonecrosis of the jaw-review of the literature and review of our own cases","volume":"6","author":"Otto","year":"2013","journal-title":"Craniomaxillofac. Trauma Reconstr."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1359\/JBMR.050817","article-title":"Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: A pooled analysis of nine clinical trials","volume":"20","author":"Miller","year":"2005","journal-title":"J. Bone Miner. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1505","DOI":"10.1093\/ndt\/gfm217","article-title":"Bisphosphonates in the renal patient","volume":"22","author":"Cunningham","year":"2007","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1161\/CIRCRESAHA.110.234278","article-title":"The regulation of valvular and vascular sclerosis by osteogenic morphogens","volume":"109","author":"Bostrom","year":"2011","journal-title":"Circ. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ejphar.2006.12.006","article-title":"Prevention of aortic calcification by etidronate in the renal failure rat model","volume":"558","author":"Tamura","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.2147\/CIA.S138002","article-title":"Bisphosphonates, atherosclerosis and vascular calcification: Update and systematic review of clinical studies","volume":"12","author":"Caffarelli","year":"2017","journal-title":"Clin. Interv. Aging"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1053\/j.ajkd.2009.12.039","article-title":"Effect of alendronate on vascular calcification in CKD stages 3 and 4: A pilot randomized controlled trial","volume":"56","author":"Toussaint","year":"2010","journal-title":"Am. J. Kidney Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1053\/j.ajkd.2011.11.037","article-title":"Bisphosphonate therapy, death, and cardiovascular events among female patients with CKD: A retrospective cohort study","volume":"59","author":"Hartle","year":"2012","journal-title":"Am. J. Kidney Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.atherosclerosis.2016.06.039","article-title":"Bisphosphonates for cardiovascular risk reduction: A systematic review and meta-analysis","volume":"252","author":"Kranenburg","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1002\/jbmr.1606","article-title":"Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX","volume":"27","author":"McCloskey","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"11","DOI":"10.4248\/BR201301003","article-title":"Osteoclasts: New Insights","volume":"1","author":"Feng","year":"2013","journal-title":"Bone Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1161\/CIRCRESAHA.108.189001","article-title":"RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway","volume":"104","author":"Panizo","year":"2009","journal-title":"Circ. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"473","DOI":"10.2353\/ajpath.2009.080957","article-title":"Inhibition of receptor activator of NF-kappaB ligand by denosumab attenuates vascular calcium deposition in mice","volume":"175","author":"Helas","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1002\/jbmr.3676","article-title":"Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial","volume":"34","author":"Iseri","year":"2019","journal-title":"J. Bone Miner. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1089\/ten.teb.2008.0565","article-title":"Translating autologous heart valve tissue engineering from bench to bed","volume":"15","author":"Hjortnaes","year":"2009","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1161\/CIRCULATIONAHA.110.006767","article-title":"Calcific aortic valve disease: Not simply a degenerative process: A review and agenda for research from the National Heart and Lung and Blood Institute Aortic Stenosis Working Group. Executive summary: Calcific aortic valve disease-2011 update","volume":"124","author":"Rajamannan","year":"2011","journal-title":"Circulation"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"iii253","DOI":"10.1093\/ndt\/gfx148.SP401","article-title":"Combination of omega-3 fatty acid and menaquinone-7 prevents progression of aortic calcification in adenine and low protein diet induced rat model","volume":"32","author":"An","year":"2017","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1016\/j.kint.2017.04.011","article-title":"Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats","volume":"92","author":"Raya","year":"2017","journal-title":"Kidney Int."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Kaesler, N., Goettsch, C., Weis, D., Schurgers, L., Hellmann, B., Floege, J., and Kramann, R. (2019). Magnesium but not nicotinamide prevents vascular calcification in experimental uraemia. Nephrol. Dial. Transplant.","DOI":"10.1093\/ndt\/gfy410"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"18406","DOI":"10.1021\/ja207628k","article-title":"Matrix Gla protein inhibits ectopic calcification by a direct interaction with hydroxyapatite crystals","volume":"133","author":"Liao","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1177\/1074248419838501","article-title":"Involvement of Vitamin K-Dependent Proteins in Vascular Calcification","volume":"24","author":"Tesfamariam","year":"2019","journal-title":"J. Cardiovasc. Pharmacol. Ther."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1161\/01.ATV.0000173313.46222.43","article-title":"Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: Undercarboxylated matrix Gla protein as marker for vascular calcification","volume":"25","author":"Schurgers","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Halder, M., Petsophonsakul, P., Akbulut, A.C., Pavlic, A., Bohan, F., Anderson, E., Maresz, K., Kramann, R., and Schurgers, L. (2019). Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040896"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/ki.2012.191","article-title":"Vitamin K intake and status are low in hemodialysis patients","volume":"82","author":"Cranenburg","year":"2012","journal-title":"Kidney Int."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3904\/kjim.2019.125","article-title":"Supplementary nutrients for prevention of vascular calcification in patients with chronic kidney disease","volume":"34","author":"Lee","year":"2019","journal-title":"Korean J. Intern. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1681\/ASN.2010040339","article-title":"Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD","volume":"22","author":"Schlieper","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1681\/ASN.2014070670","article-title":"Calcification Propensity and Survival among Renal Transplant Recipients","volume":"27","author":"Keyzer","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"30","DOI":"10.5414\/CNP73030","article-title":"Metal ion and vitamin adsorption profiles of phosphate binder ion-exchange resins","volume":"73","author":"Takagi","year":"2010","journal-title":"Clin. Nephrol."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Neradova, A., Schumacher, S.P., Hubeek, I., Lux, P., Schurgers, L.J., and Vervloet, M.G. (2017). Phosphate binders affect vitamin K concentration by undesired binding, an in vitro study. BMC Nephrol., 18.","DOI":"10.1186\/s12882-017-0560-3"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Jansz, T.T., Neradova, A., van Ballegooijen, A.J., Verhaar, M.C., Vervloet, M.G., Schurgers, L.J., and van Jaarsveld, B.C. (2018). The role of kidney transplantation and phosphate binder use in vitamin K status. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0203157"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Aoun, M., Makki, M., Azar, H., Matta, H., and Chelala, D.N. (2017). High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: Risk factors and response to vitamin K2, A pre-post intervention clinical trial. BMC Nephrol., 18.","DOI":"10.1186\/s12882-017-0609-3"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1053\/j.ajkd.2011.10.041","article-title":"Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: A randomized trial","volume":"59","author":"Westenfeld","year":"2012","journal-title":"Am. J. Kidney Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1093\/ckj\/sfv146","article-title":"The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: Ongoing randomized controlled trials","volume":"9","author":"Caluwe","year":"2016","journal-title":"Clin. Kidney J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"631","DOI":"10.20452\/pamw.3041","article-title":"Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3\u20135","volume":"125","author":"Kurnatowska","year":"2015","journal-title":"Pol. Arch. Med. Wewn."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Shi, H., Jia, J., Li, D., and Lin, S. (2013). Vitamin D supplementation and mortality risk in chronic kidney disease: A meta-analysis of 20 observational studies. BMC Nephrol., 14.","DOI":"10.1186\/1471-2369-14-199"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.atherosclerosis.2011.10.023","article-title":"Vitamin D deficiency and endothelial dysfunction in non-dialysis chronic kidney disease patients","volume":"220","author":"Chitalia","year":"2012","journal-title":"Atherosclerosis"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.2215\/CJN.10791016","article-title":"Randomized Controlled Trial for the Effect of Vitamin D Supplementation on Vascular Stiffness in CKD","volume":"12","author":"Levin","year":"2017","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3100","DOI":"10.1681\/ASN.2017010003","article-title":"A Randomized Trial of Vitamin D Supplementation on Vascular Function in CKD","volume":"28","author":"Kumar","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1053\/j.jrn.2018.12.002","article-title":"The Effect of Long-Term Cholecalciferol Supplementation on Vascular Calcification in Chronic Kidney Disease Patients With Hypovitaminosis D","volume":"29","author":"Samaan","year":"2019","journal-title":"J. Ren. Nutr."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"204","DOI":"10.5301\/JN.2011.8429","article-title":"Incident isolated 1,25(OH)(2)D(3) deficiency is more common than 25(OH)D deficiency in CKD","volume":"25","author":"Levin","year":"2012","journal-title":"J. Nephrol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1093\/ndt\/gfs520","article-title":"Magnesium prevents phosphate-induced calcification in human aortic vascular smooth muscle cells","volume":"28","author":"Louvet","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"i52","DOI":"10.1093\/ndtplus\/sfr167","article-title":"Magnesium and outcomes in patients with chronic kidney disease: Focus on vascular calcification, atherosclerosis and survival","volume":"5","author":"Massy","year":"2012","journal-title":"Clin. Kidney J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1159\/000345243","article-title":"Vascular actions of aldosterone","volume":"50","author":"Briet","year":"2013","journal-title":"J. Vasc. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1007\/s11255-019-02073-w","article-title":"Hypomagnesemia is not an independent risk factor for mortality in Japanese maintenance hemodialysis patients","volume":"51","author":"Mizuiri","year":"2019","journal-title":"Int. Urol. Nephrol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1159\/000498957","article-title":"Baseline Serum Magnesium Level and Its Variability in Maintenance Hemodialysis Patients: Associations with Mortality","volume":"44","author":"Wu","year":"2019","journal-title":"Kidney Blood Press. Res."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Sakaguchi, Y., Fujii, N., Shoji, T., Hayashi, T., Rakugi, H., Iseki, K., Tsubakihara, Y., Isaka, Y., and Committee of Renal Data Registry of the Japanese Society for Dialysis Therapy (2014). Magnesium modifies the cardiovascular mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis: A cohort study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0116273"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Cai, K., Luo, Q., Dai, Z., Zhu, B., Fei, J., Xue, C., and Wu, D. (2016). Hypomagnesemia Is Associated with Increased Mortality among Peritoneal Dialysis Patients. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152488"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1053\/j.ajkd.2019.01.024","article-title":"Serum Calcification Propensity and Coronary Artery Calcification Among Patients With CKD: The CRIC (Chronic Renal Insufficiency Cohort) Study","volume":"73","author":"Bundy","year":"2019","journal-title":"Am. J. Kidney Dis."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1159\/000346427","article-title":"Effect of magnesium supplementation on carotid intima-media thickness and flow-mediated dilatation among hemodialysis patients: A double-blind, randomized, placebo-controlled trial","volume":"69","author":"Mortazavi","year":"2013","journal-title":"Eur. Neurol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s11255-008-9410-3","article-title":"Magnesium supplementation helps to improve carotid intima media thickness in patients on hemodialysis","volume":"40","author":"Turgut","year":"2008","journal-title":"Int. Urol. Nephrol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"e016795","DOI":"10.1136\/bmjopen-2017-016795","article-title":"The effect of magnesium supplementation on vascular calcification in chronic kidney disease-a randomised clinical trial (MAGiCAL-CKD): Essential study design and rationale","volume":"7","author":"Bressendorff","year":"2017","journal-title":"BMJ Open"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/bcp.13863","article-title":"A phase 1b randomized, placebo-controlled clinical trial with SNF472 in haemodialysis patients","volume":"85","author":"Salcedo","year":"2019","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1111\/bcp.13752","article-title":"First-time-in-human randomized clinical trial in healthy volunteers and haemodialysis patients with SNF472, a novel inhibitor of vascular calcification","volume":"84","author":"Perello","year":"2018","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1002\/ptr.5083","article-title":"Puerarin: A review of pharmacological effects","volume":"28","author":"Zhou","year":"2014","journal-title":"Phytother. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ejphar.2019.05.023","article-title":"Puerarin inhibits vascular calcification of uremic rats","volume":"855","author":"Liu","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1097\/MOL.0b013e3283613a7d","article-title":"Novel benefits of peroxisome proliferator-activated receptors on cardiovascular risk","volume":"24","author":"Millar","year":"2013","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1097\/HJH.0b013e3282f52c36","article-title":"Effects of telmisartan, a unique angiotensin receptor blocker with selective peroxisome proliferator-activated receptor-gamma-modulating activity, on nitric oxide bioavailability and atherosclerotic change","volume":"26","author":"Ikejima","year":"2008","journal-title":"J. Hypertens."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1159\/000491025","article-title":"Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients","volume":"48","author":"Bostom","year":"2018","journal-title":"Am. J. Nephrol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/ki.2012.40","article-title":"Activation of nuclear factor-kappa B accelerates vascular calcification by inhibiting ankylosis protein homolog expression","volume":"82","author":"Zhao","year":"2012","journal-title":"Kidney Int."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Yoshida, T., Yamashita, M., Horimai, C., and Hayashi, M. (2017). Smooth Muscle-Selective Nuclear Factor-kappaB Inhibition Reduces Phosphate-Induced Arterial Medial Calcification in Mice With Chronic Kidney Disease. J. Am. Heart Assoc., 6.","DOI":"10.1161\/JAHA.117.007248"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/jbmr.539","article-title":"The antioxidant tempol ameliorates arterial medial calcification in uremic rats: Important role of oxidative stress in the pathogenesis of vascular calcification in chronic kidney disease","volume":"27","author":"Yamada","year":"2012","journal-title":"J. Bone Miner. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"F967","DOI":"10.1152\/ajprenal.00669.2014","article-title":"Spironolactone ameliorates arterial medial calcification in uremic rats: The role of mineralocorticoid receptor signaling in vascular calcification","volume":"309","author":"Tatsumoto","year":"2015","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"745","DOI":"10.2215\/CJN.05450513","article-title":"Biomarkers of vascular calcification and mortality in patients with ESRD","volume":"9","author":"Scialla","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1159\/000381937","article-title":"Serum Soluble Klotho Level Is Associated with Abdominal Aortic Calcification in Patients on Maintenance Hemodialysis","volume":"40","author":"Cai","year":"2015","journal-title":"Blood Purif."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1681\/ASN.2012030240","article-title":"Nanoparticle-based test measures overall propensity for calcification in serum","volume":"23","author":"Pasch","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"13333","DOI":"10.1074\/jbc.M210868200","article-title":"Structural basis of calcification inhibition by alpha 2-HS glycoprotein\/fetuin-A. Formation of colloidal calciprotein particles","volume":"278","author":"Heiss","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1681\/ASN.2013060635","article-title":"Serum calcification propensity predicts all-cause mortality in predialysis CKD","volume":"25","author":"Smith","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"13368","DOI":"10.1038\/s41598-017-12859-6","article-title":"Worsening calcification propensity precedes all-cause and cardiovascular mortality in haemodialyzed patients","volume":"7","author":"Lorenz","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/ajt.13443","article-title":"Serum Calcification Propensity Is a Strong and Independent Determinant of Cardiac and All-Cause Mortality in Kidney Transplant Recipients","volume":"16","author":"Dahle","year":"2016","journal-title":"Am. J. Transplant."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1161\/CIRCULATIONAHA.116.027011","article-title":"Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation: Results From a Prospective Interventional Proof-of-Concept Study","volume":"135","author":"Brandenburg","year":"2017","journal-title":"Circulation"}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/3\/181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:06:58Z","timestamp":1760173618000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/3\/181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,14]]},"references-count":119,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["toxins12030181"],"URL":"https:\/\/doi.org\/10.3390\/toxins12030181","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,14]]}}}