Efficacy of Cilastatin Sodium in a Translational Large Animal Crush Syndrome Model

Efficacy of Cilastatin Sodium in a Translational Large Animal Crush Syndrome Model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Efficacy of Cilastatin Sodium in a Translational Large Animal Crush Syndrome Model Michael Hutchens, Adam Munhall, Mahaba Eiwaz, Jessica Hebert, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7021997/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract Background: Crush syndrome (consisting of hyperkalemia, acidosis, hypocalcemia, and acute kidney injury), is the second-most common cause of death in earthquakes, and a frequent cause of critical illness after burn, blast, and prolonged immobility. No specific treatment exists, and supportive treatment is highly burdensome, contributing to deaths in austere environments, especially disasters and conflicts. Therefore, there is urgent need for specific treatment which reduces burden of care. Crush syndrome is dependent on the renal megalin-dependent endocytic system. We investigated whether cilastatin sodium, a megalin inhibitor which is US Food and Drug Administration-approved for another purpose, has efficacy as a crush syndrome treatment in a highly translational large animal trauma model. Methods: Anesthetized 40 kg pigs were subjected to blunt muscle injury and assessed during 48h protocolized critical care management. Cilastatin sodium or vehicle was administered 30 minutes after injury in randomized, blinded fashion. Renal function and injury were assessed by repeated quantification of iohexol clearance, serial plasma assessment, and histopathologic analysis. Linear mixed models and Kaplan-Meir analysis were used to assess differences, and a power estimate for a clinical trial was performed. Results: Here we show that administration of cilastatin ameliorated crush syndrome, resulting in increased measured glomerular filtration rate, reduced creatinine, reduced need for treatment of hyperkalemia, and reduced histopathologic kidney damage. Animals receiving cilastatin excreted more myoglobin in the urine and were more likely to recover from acute kidney injury. Conclusion: Cilastatin sodium has efficacy to ameliorate crush syndrome in a translational large animal model. Health sciences/Nephrology/Kidney diseases/Acute kidney injury Health sciences/Medical research/Drug development crush syndrome trauma earthquake disaster blast acute kidney injury hyperkalemia myoglobin repurposing creatine kinase translation cilastatin megalin Full Text Additional Declarations There is NO Competing Interest. Supplementary figures are not available with this version Cite Share Download PDF Status: Published Journal Publication published 12 Mar, 2026 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7021997","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":483477543,"identity":"27823ab4-aae7-41bd-bbe7-3413172feb95","order_by":0,"name":"Michael 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Model","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"crush syndrome, trauma, earthquake, disaster, blast, acute kidney injury, hyperkalemia, myoglobin, repurposing, creatine kinase, translation, cilastatin, megalin","lastPublishedDoi":"10.21203/rs.3.rs-7021997/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7021997/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Crush syndrome (consisting of hyperkalemia, acidosis, hypocalcemia, and acute kidney injury), is the second-most common cause of death in earthquakes, and a frequent cause of critical illness after burn, blast, and prolonged immobility. No specific treatment exists, and supportive treatment is highly burdensome, contributing to deaths in austere environments, especially disasters and conflicts. Therefore, there is urgent need for specific treatment which reduces burden of care. Crush syndrome is dependent on the renal megalin-dependent endocytic system. We investigated whether cilastatin sodium, a megalin inhibitor which is US Food and Drug Administration-approved for another purpose, has efficacy as a crush syndrome treatment in a highly translational large animal trauma model.\u003c/p\u003e\n\u003cp\u003eMethods: Anesthetized 40 kg pigs were subjected to blunt muscle injury and assessed during 48h protocolized critical care management. Cilastatin sodium or vehicle was administered 30 minutes after injury in randomized, blinded fashion. Renal function and injury were assessed by repeated quantification of iohexol clearance, serial plasma assessment, and histopathologic analysis. Linear mixed models and Kaplan-Meir analysis were used to assess differences, and a power estimate for a clinical trial was performed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: Here we show that administration of cilastatin ameliorated crush syndrome, resulting in increased measured glomerular filtration rate, reduced creatinine, reduced need for treatment of hyperkalemia, and reduced histopathologic kidney damage. Animals receiving cilastatin excreted more myoglobin in the urine and were more likely to recover from acute kidney injury.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: Cilastatin sodium has efficacy to ameliorate crush syndrome in a translational large animal model.\u003c/p\u003e","manuscriptTitle":"Efficacy of Cilastatin Sodium in a Translational Large Animal Crush Syndrome Model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-11 05:47:48","doi":"10.21203/rs.3.rs-7021997/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dae5bbc1-b37d-46a9-a30d-2fcc613adfd8","owner":[],"postedDate":"July 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51336636,"name":"Health sciences/Nephrology/Kidney diseases/Acute kidney injury"},{"id":51336637,"name":"Health sciences/Medical research/Drug development"}],"tags":[],"updatedAt":"2026-04-28T07:11:06+00:00","versionOfRecord":{"articleIdentity":"rs-7021997","link":"https://doi.org/10.1038/s43856-026-01411-1","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2026-03-12 04:00:00","publishedOnDateReadable":"March 12th, 2026"},"versionCreatedAt":"2025-07-11 05:47:48","video":"","vorDoi":"10.1038/s43856-026-01411-1","vorDoiUrl":"https://doi.org/10.1038/s43856-026-01411-1","workflowStages":[]},"version":"v1","identity":"rs-7021997","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7021997","identity":"rs-7021997","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}