{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T05:03:35Z","timestamp":1792904615626,"version":"4.5.0"},"reference-count":30,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008108","name":"Taipei Tzu Chi Hospital","doi-asserted-by":"publisher","award":["TCRD-TPE-106-RT-5"],"award-info":[{"award-number":["TCRD-TPE-106-RT-5"]}],"id":[{"id":"10.13039\/501100008108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008108","name":"Taipei Tzu Chi Hospital","doi-asserted-by":"publisher","award":["TCRD-TPE-108-15"],"award-info":[{"award-number":["TCRD-TPE-108-15"]}],"id":[{"id":"10.13039\/501100008108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008108","name":"Taipei Tzu Chi Hospital","doi-asserted-by":"publisher","award":["TCRD-TPE-108-19"],"award-info":[{"award-number":["TCRD-TPE-108-19"]}],"id":[{"id":"10.13039\/501100008108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008108","name":"Taipei Tzu Chi Hospital","doi-asserted-by":"publisher","award":["TCMF-EP 108-06"],"award-info":[{"award-number":["TCMF-EP 108-06"]}],"id":[{"id":"10.13039\/501100008108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008108","name":"Taipei Tzu Chi Hospital","doi-asserted-by":"publisher","award":["TCAS-108-02"],"award-info":[{"award-number":["TCAS-108-02"]}],"id":[{"id":"10.13039\/501100008108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 105-2314-B-303-014-MY3"],"award-info":[{"award-number":["MOST 105-2314-B-303-014-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 107-2314-B-303-021"],"award-info":[{"award-number":["MOST 107-2314-B-303-021"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-303-002-MY3"],"award-info":[{"award-number":["MOST 108-2314-B-303-002-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2314-B-303-004-MY3"],"award-info":[{"award-number":["MOST 108-2314-B-303-004-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Peripheral artery disease (PAD) is highly prevalent among patients with chronic kidney disease (CKD) and portends a very poor prognosis. Indoxyl sulfate has been shown to induce atherothrombosis and impaired neovascularization in uremic mice. However, there is no clinical evidence regarding the role of indoxyl sulfate in PAD associated with CKD. We examined associations between indoxyl sulfate and incident symptomatic lower extremity PAD events as well as major adverse cardiovascular events (MACE) and all-cause mortality using Cox proportional hazards models in a prospective cohort of 200 hemodialysis patients free of PAD at baseline. Patients were considered as having PAD if they developed PAD symptoms confirmed by an ankle-brachial index with waveforms, duplex ultrasound or angiography, and\/or major adverse limb events including revascularization and amputation. During a median follow-up of 6.5 years, 37 patients (18.5%) experienced incident symptomatic PAD. MACE occurred in 52 patients, and a total of 85 patients died. After adjusting for traditional risk factors for PAD, including age, current smoking, diabetes, and cardiovascular disease, indoxyl sulfate was significantly associated with the risk of PAD (hazard ratio (HR), 1.19 for every 10-\u03bcg\/mL increase in indoxyl sulfate; 95% confidence interval (CI), 1.05\u20131.35). However, indoxyl sulfate was not associated with risk of MACE (HR, 1.00; 95% CI, 0.90\u20131.12) or death from any cause (HR, 0.98; 95% CI, 0.90\u20131.07). Indoxyl sulfate was associated with incident symptomatic PAD but not with MACE or all-cause mortality, suggesting that indoxyl sulfate toxicity may be unique to PAD among hemodialysis patients.<\/jats:p>","DOI":"10.3390\/toxins12110696","type":"journal-article","created":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T19:51:31Z","timestamp":1604346691000},"page":"696","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Indoxyl Sulfate and Incident Peripheral Artery Disease in Hemodialysis Patients"],"prefix":"10.3390","volume":"12","author":[{"given":"Ting-Yun","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Hua","family":"Chou","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7640-7702","authenticated-orcid":false,"given":"Hsuan-Li","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szu-Chun","family":"Hung","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Tzu Chi University, Hualien 970, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"key":"ref_1","unstructured":"United States Renal Data System (2018). 2018 USRDS Annual Data Report: Cardiovascular Disease in Patients with CKD, National Institute of Diabetes and Digestive and Kidney Diseases."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1001\/jamainternmed.2018.2436","article-title":"Trends in rates of lower extremity amputation among patients with end-stage renal disease who receive dialysis","volume":"178","author":"Franz","year":"2018","journal-title":"JAMA Intern. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.amjcard.2012.02.061","article-title":"CRIC Investigators. Risk factors for peripheral arterial disease among patients with chronic kidney disease","volume":"110","author":"Chen","year":"2012","journal-title":"Am. J. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1093\/ndt\/gfv418","article-title":"Traditional and non-traditional risk factors for incident peripheral arterial disease among patients with chronic kidney disease","volume":"31","author":"Chen","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1681\/ASN.V132497","article-title":"Peripheral vascular disease risk factors among patients undergoing hemodialysis","volume":"13","author":"Hsu","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1681\/ASN.2005111204","article-title":"Kidney function and risk of peripheral arterial disease: Results from the Atherosclerosis Risk in Communities (ARIC) Study","volume":"18","author":"Wattanakit","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1016\/j.kint.2015.11.020","article-title":"Indoxyl sulfate suppresses endothelial progenitor cell\u2013mediated neovascularization","volume":"89","author":"Hung","year":"2016","journal-title":"Kidney Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1161\/CIRCULATIONAHA.105.607390","article-title":"Peripheral arterial disease in patients with end-stage renal disease: Observations from the Dialysis Outcomes and Practice Patterns Study (DOPPS)","volume":"114","author":"Rajagopalan","year":"2006","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/j.1523-1755.2004.00420.x","article-title":"Predictors of amputation and survival following lower extremity revascularization in hemodialysis patients","volume":"65","author":"Jaar","year":"2004","journal-title":"Kidney Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1067\/mva.2002.128297","article-title":"A decade experience with infrainguinal revascularization in a dialysis-dependent patient population","volume":"36","author":"Ramdev","year":"2002","journal-title":"J. Vasc. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e005022","DOI":"10.1161\/JAHA.116.005022","article-title":"Indoxyl sulfate: A novel cardiovascular risk factor in chronic kidney disease","volume":"6","author":"Hung","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1111\/j.1538-7836.2009.03540.x","article-title":"Levels of circulating endothelial progenitor cells are related to uremic toxins and vascular injury in hemodialysis patients","volume":"7","author":"Dou","year":"2009","journal-title":"J. Thromb. Haemost."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1038\/sj.ki.5000340","article-title":"Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells","volume":"69","author":"Yamamoto","year":"2006","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1681\/ASN.2012030281","article-title":"Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall","volume":"24","author":"Pletinck","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1093\/ndt\/gfr453","article-title":"Serum free p-cresyl sulfate levels predict cardiovascular and all-cause mortality in elderly hemodialysis patients\u2013a prospective cohort study","volume":"27","author":"Wu","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1016\/j.kint.2017.05.012","article-title":"Results of the HEMO Study suggest that p-cresol sulfate and indoxyl sulfate are not associated with cardiovascular outcomes","volume":"92","author":"Shafi","year":"2017","journal-title":"Kidney Int."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1681\/ASN.2013101062","article-title":"The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: A systematic review","volume":"25","author":"Vanholder","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2330","DOI":"10.1161\/CIRCULATIONAHA.118.035432","article-title":"Lipoprotein particle profiles, standard lipids, and peripheral artery disease incidence","volume":"138","author":"Aday","year":"2018","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1016\/j.jacc.2018.08.002","article-title":"Pathology of Peripheral Artery Disease in Patients With Critical Limb Ischemia","volume":"72","author":"Narula","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/ki.2013.133","article-title":"Indolic uremic solutes increase tissue factor production in endothelial cells by the aryl hydrocarbon receptor pathway","volume":"84","author":"Gondouin","year":"2013","journal-title":"Kidney Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1161\/ATVBAHA.117.309846","article-title":"Tissue factor: An essential mediator of hemostasis and trigger of thrombosis","volume":"38","author":"Grover","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.kint.2015.12.030","article-title":"The harmful effect of indoxyl sulfate on neovascularization in chronic kidney disease","volume":"89","author":"Dou","year":"2016","journal-title":"Kidney Int."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1681\/ASN.2015010068","article-title":"Serum indoxyl sulfate associates with post-angioplasty thrombosis of dialysis grafts","volume":"27","author":"Wu","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Eloot, S., Van Biesen, W., Roels, S., Delrue, W., Schepers, E., Dhondt, A., Vanholder, R., and Glorieux, G. (2017). Spontaneous variability of pre-dialysis concentrations of uremic toxins over time in stable hemodialysis patients. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0186010"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1681\/ASN.2013121283","article-title":"The cardiovascular effect of the uremic solute indole-3 acetic acid","volume":"26","author":"Dou","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"US Preventive Services Task Force, Curry, S.J., Krist, A.H., Owens, D.K., Barry, M.J., Caughey, A.B., Davidson, K.W., Doubeni, C.A., Epling, J.W., and Kemper, A.R. (2018). Screening for Peripheral Artery Disease and Cardiovascular Disease Risk Assessment With the Ankle-Brachial Index: US Preventive Services Task Force Recommendation Statement. JAMA, 320, 177\u2013183.","DOI":"10.1001\/jama.2018.8357"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1007\/s00216-012-5929-3","article-title":"Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography\/tandem mass spectrometry and their effects on endothelial ROS production","volume":"403","author":"Itoh","year":"2012","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1681\/ASN.V451205","article-title":"Second generation logarithmic estimates of single-pool variable volume Kt\/V: An analysis of error","volume":"4","author":"Daugirdas","year":"1993","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1681\/ASN.V75780","article-title":"Equations for normalized protein catabolic rate based on two-point modeling of hemodialysis urea kinetics","volume":"7","author":"Depner","year":"1996","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2199","DOI":"10.2215\/CJN.09451209","article-title":"Detection of peripheral artery disease by duplex ultrasonography among hemodialysis patients","volume":"5","author":"Ogata","year":"2010","journal-title":"Clin. J. Am. Soc. Nephrol."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/11\/696\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:28:21Z","timestamp":1760178501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/12\/11\/696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,2]]},"references-count":30,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["toxins12110696"],"URL":"https:\/\/doi.org\/10.3390\/toxins12110696","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,2]]}}}