{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:58:40Z","timestamp":1791313120915,"version":"4.3.1"},"reference-count":115,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 109-2314-B-002-193-MY3"],"award-info":[{"award-number":["MOST 109-2314-B-002-193-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ter-Zer Foundation for Educational Achievement","award":["."],"award-info":[{"award-number":["."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small\/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia\/muscle wasting, cognitive impairment\/cognitive frailty, osteoporosis\/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor \u03b3 coactivator 1-\u03b1 (PGC-1\u03b1), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)\/nuclear factor-\u03baB (NF-\u03baB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients\u2019 outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.<\/jats:p>","DOI":"10.3390\/ijms22126270","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T13:31:39Z","timestamp":1623331899000},"page":"6270","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2892-7986","authenticated-orcid":false,"given":"Chia-Ter","family":"Chao","sequence":"first","affiliation":[{"name":"Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital BeiHu Branch, Taipei 10845, Taiwan"},{"name":"Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 100233, Taiwan"},{"name":"Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei 100255, Taiwan"},{"name":"Nephrology Division, Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100233, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hua","family":"Lin","sequence":"additional","affiliation":[{"name":"Nephrology Division, Department of Internal Medicine, National Defense Medical Center, Taipei 11490, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1681\/ASN.2011121175","article-title":"Normal and pathologic concentrations of uremic toxins","volume":"23","author":"Duranton","year":"2012","journal-title":"J. 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