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Early, targeted intervention can help mitigate its impact. CK273 is a urinary peptide classifier previously validated in a prospective clinical trial for the early detection of nephropathy. We hypothesized that drug-induced molecular changes in the urinary peptidome could be predicted in silico and guide selecting interventions for individual patients.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>The efficacy of the urinary peptidomic classifier CKD273 in predicting major adverse kidney events (\u2265\u200940% decline in estimated glomerular filtration rate or kidney failure -median follow-up: 1.50 (95%CI 0.35, 5.0) years), was confirmed in a retrospective cohort of 935 participants. In silico prediction of treatment effects from four drug-based interventions (Mineralocorticoid receptor antagonist, Sodium-glucose co-transporter 2 inhibitor, Glucagon-like peptide-1 receptor agonist, and Angiotensin receptor blocker), dietary intervention (olive oil), and exercise was performed based on: a) individual baseline urinary peptide profiles, and b) previously defined fold changes in peptide abundance after treatment in clinical trials. Following recalibration to align with outcomes of these trials, CKD273 scores were calculated for each patient after in silico treatment. For combination treatments, the effects of multiple interventions were combined.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Simulated interventions demonstrated a significant reduction in median CKD273 scores, from 0.57 (IQR: 0.19\u20130.81) before to 0.039 (IQR: \u22120.192\u20130.363) after the most beneficial intervention (paired Wilcoxon test, <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.0001). The combination of all available treatments was not the most frequently predicted optimal intervention. Patients with higher baseline CKD273 scores required more complex intervention combinations to achieve the greatest score reduction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study supports the feasibility of in silico predicting effects of therapeutic interventions on CKD progression. By identifying the most beneficial treatment combinations for individual patients, this approach paves the way for precision medicine trials in CKD. A prospective study is currently being planned to validate the in silico-guided intervention approach and determine its exact benefits on patient-relevant outcomes.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12967-025-06977-3","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T12:26:24Z","timestamp":1755779184000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In silico prediction of optimal multifactorial intervention in chronic kidney disease"],"prefix":"10.1186","volume":"23","author":[{"given":"Agnieszka","family":"Latosinska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna K.","family":"Mina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thi Minh Nghia","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor","family":"Golovko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gert","family":"Mayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Rossing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Staessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Delles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Beige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Griet","family":"Glorieux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost P.","family":"Schanstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Vlahou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karlheinz","family":"Peter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Rychl\u00edk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Archie","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Rupprecht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Persson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0323-0306","authenticated-orcid":false,"given":"Harald","family":"Mischak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justyna","family":"Siwy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,21]]},"reference":[{"key":"6977_CR1","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.amjmed.2015.08.025","volume":"129","author":"JA Vassalotti","year":"2016","unstructured":"Vassalotti JA, Centor R, Turner BJ, Greer RC, Choi M, Sequist TD. 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Proteomes. 2021;9:32.","journal-title":"Proteomes"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-06977-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-025-06977-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-025-06977-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T04:33:53Z","timestamp":1757478833000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-025-06977-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,21]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["6977"],"URL":"https:\/\/doi.org\/10.1186\/s12967-025-06977-3","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,21]]},"assertion":[{"value":"31 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted according to the guidelines of the Declaration of Helsinki. All datasets were fully anonymized and from previous studies. The ethics committee of the Hannover Medical School Germany waived ethical approval under the reference number 3116\u20132016 for all studies involving re-use of data from anonymized urine samples.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"HM is the co-founder and co-owner of Mosaiques Diagnostics (Hannover, Germany). He filed a patent application on the in silico driven treatment prediction model using urinary peptidomics (EP 23734620.0). AL, TMNN, IG, IM and JS are employed by Mosaiques Diagnostics. ALC is member of the BCS Chair Programme Committee. HR has received consulting fees from Otsuka (Advisory Board Sebiprenlimab), Bayer Vital (Advisory Board Herz und Niere) and Stada (Neue Dg und Th Optionen), payment or honoraria from AstraZeneca (Therapien der Zukunft, DGfN), Boehringer (Herz Forum Heidelberg), Pfizer (Kardiologie Hand in Hand im Frankenland), Vifor (ANCA-Vaskulitis) and support for attending meetings and\/or travel from Alexion (DGfN) and AstraZeneca (ERA). GG is co-chair of the European Uremic Toxin Workgroup (EUTox) and was supported for attending meetings and\/or travel from the COST ACTION PerMediK (CA21165). JPS was supported by the ERA PerMed SIGNAL project (Agence Nationale de le Recherche under grant number ANR-22-PERM-0002\u201306). AO has received grants from Sanofi (Grants to institution: IIS-FJD UAM) and is Director of the Catedra Astrazeneca-UAM of chronic kidney disease and electrolytes (Grants to Universidad Autonoma de Madrid (UAM)). AO has also received consultancy fees from Astellas, Astrazeneca, Bioporto, Boehringer Ingelheim, Fresenius Medical Care, GSK, Bayer, Sanofi- Genzyme, Lilly, Chiesi, Otsuka, Novo-Nordisk, Sysmex, speaker fees from Astellas, Astrazeneca, Bioporto, Boehringer Ingelheim, Fresenius Medical Care, GSK, Bayer, Sanofi- Genzyme, Sobi, Menarini, Lilly, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma and Spafarma, and travel support (Payments to travel agency or hotel for travel\/stay) from Astellas, Astrazeneca, Fresenius Medical Care, Boehringer- Ingelheim, Bayer, Sanofi-Genzyme, Chiesi, Sobi, Bayer. He is a member of the Council ERA. SOMANE. PR has received grants (to the institution) by Novo Nordisk, Bayer, Astra Zeneca. He also received honoraria to the institution for education, steering group membership and\/or consultancy from Abbott, Bayer, Boehringer Ingelheim, Astra Zeneca, Novo Nordisk, Gilead, Sanofi, Daiichi Sankyo. His institution has also received study drugs from Astra Zeneca, Lexicon, Novo Nordisk, Bayer. Remaining authors have no conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"During the preparation of this work the author(s) used [ChatGPT by OpenAI, Grammarly]. in order to improve readability and language, including grammar. After using this tool, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Generative AI and AI-assisted technologies"}}],"article-number":"943"}}