{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:16:29Z","timestamp":1785420989140,"version":"3.56.0"},"reference-count":185,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["114-2314-B-182A-048"],"award-info":[{"award-number":["114-2314-B-182A-048"]}]},{"name":"National Science and Technology Council, Taiwan","award":["114-2314-B-182A-036-MY3"],"award-info":[{"award-number":["114-2314-B-182A-036-MY3"]}]},{"award":["114-2314-B-182A-048"],"award-info":[{"award-number":["114-2314-B-182A-048"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["114-2314-B-182A-036-MY3"],"award-info":[{"award-number":["114-2314-B-182A-036-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Cardiovascular\u2013kidney\u2013metabolic (CKM) syndrome is a systemic, interdependent disorder arising from the convergence of metabolic dysfunction, chronic kidney disease, and cardiovascular pathology. Anchored in the Developmental Origins of Health and Disease (DOHaD) framework, this review advances a \u201cparallel hit\u201d model, primarily based on evidence from experimental animal studies, particularly rodent models, posited that early-life environmental insults concurrently program structural and functional vulnerabilities in both renal and central nervous system hubs. These early perturbations prime susceptibility long before clinical manifestations emerge. CKM progression is conceptualized as a two-stage trajectory, with an initial phase of parallel programming affecting kidney and brain development, followed by a transition to maladaptive bidirectional crosstalk. In the later phase, heightened efferent sympathetic outflow and aberrant afferent renal signaling\u2014potentiated by uremic toxin accumulation, neuroinflammation, and blood\u2013brain barrier disruption\u2014drive a self-perpetuating cycle that accelerates cardiorenal and metabolic injury. Key integrative mechanisms, including oxidative stress, chronic low-grade inflammation, mitochondrial dysfunction, and gut microbiota dysbiosis, serve as convergent pathways linking early-life exposures to adult CKM phenotypes. These pathways not only sustain disease progression but also represent actionable therapeutic targets. Importantly, this framework underscores the translational potential of early-life \u201creprogramming\u201d strategies. Interventions such as precision nutrition, antioxidant supplementation, microbiota-directed therapies (including prebiotics, probiotics, and postbiotics), and mechanism-based pharmacotherapies may mitigate or reverse maladaptive programming. However, much of the current mechanistic evidence remains preclinical, and further human studies are needed to validate these pathways and therapeutic approaches. Collectively, this dual-hub paradigm reframes CKM syndrome as a life-course continuum rather than a late-stage comorbidity cluster, emphasizing the necessity of early, mechanism-driven interventions to stabilize the brain\u2013kidney axis and improve long-term cardiovascular\u2013kidney\u2013metabolic outcomes.<\/jats:p>","DOI":"10.3390\/antiox15060769","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T05:52:11Z","timestamp":1782453131000},"page":"769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Parallel Programming to Bidirectional Crosstalk: The Brain\u2013Kidney Axis in Cardiovascular\u2013Kidney\u2013Metabolic Syndrome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7470-528X","authenticated-orcid":false,"given":"Chien-Ning","family":"Hsu","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan"},{"name":"Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"},{"name":"School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7059-6407","authenticated-orcid":false,"given":"You-Lin","family":"Tain","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan 333, Taiwan"},{"name":"Doctoral Program of Clinical and Experimental Medicine, National Sun Yat-Sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1016\/S0140-6736(24)00757-8","article-title":"GBD 2021 Diseases and Injuries Collaborators. 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