{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:00:53Z","timestamp":1788843653593,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sybilla-Hesse Foundation"},{"name":"Open Medicine Foundation Canada"},{"name":"Open Medicine Foundation (USA)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Myalgic Encephalomyelitis (ME) is a complex, multisystem disorder with poorly understood pathophysiological mechanisms. SMPDL3B, a membrane-associated protein expressed in renal podocytes, is essential for lipid raft integrity and glomerular barrier function. We hypothesize that reduced membrane-bound SMPDL3B may contribute to podocyte dysfunction and impaired renal physiology in ME. To investigate this, we quantified soluble SMPDL3B in plasma and urine as a surrogate marker of membrane-bound SMPDL3B status and assessed renal clearance and plasma metabolomic profiles. In a cross-sectional study of 56 ME patients and 16 matched healthy controls, ME patients exhibited significantly lower urine-to-plasma ratios of soluble SMPDL3B and reduced renal clearance, suggesting podocyte-related abnormalities. Plasma metabolomics revealed dysregulation of metabolites associated with renal impairment, including succinic acid, benzoic acid, phenyllactic acid, 1,5-anhydroglucitol, histidine, and citrate. In ME patients, plasma SMPDL3B levels inversely correlated with 1,5-anhydroglucitol concentrations and renal clearance. Multivariable modeling identified the urine-to-plasma SMPDL3B ratio as an independent predictor of clearance. Female ME patients showed more pronounced SMPDL3B alterations, reduced clearance, and greater symptom severity. Non-linear associations between soluble SMPDL3B and lipid species further suggest systemic metabolic remodeling. These findings support soluble SMPDL3B as a potential non-invasive biomarker of renal-podocyte involvement in ME, highlighting sex-specific differences that may inform future therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms26188882","type":"journal-article","created":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T12:08:16Z","timestamp":1757678896000},"page":"8882","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Circulating Levels of SMPDL3B Define Metabolic Endophenotypes and Subclinical Kidney Alterations in Myalgic Encephalomyelitis"],"prefix":"10.3390","volume":"26","author":[{"given":"Bita","family":"Rostami-Afshari","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3577-3551","authenticated-orcid":false,"given":"Wesam","family":"Elremaly","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil R.","family":"McGregor","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville, VIC 3010, Australia"},{"name":"Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Flemington Road, Parkville, VIC 3010, Australia"},{"name":"The Open Medicine Foundation ME\/CFS Collaborative Research Centre, Bio21 Molecular Science and Biochemistry Institute, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0171-6820","authenticated-orcid":false,"given":"Katherine Jin Kai","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville, VIC 3010, Australia"},{"name":"The Open Medicine Foundation ME\/CFS Collaborative Research Centre, Bio21 Molecular Science and Biochemistry Institute, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5964-5618","authenticated-orcid":false,"given":"Christopher W.","family":"Armstrong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville, VIC 3010, Australia"},{"name":"The Open Medicine Foundation ME\/CFS Collaborative Research Centre, Bio21 Molecular Science and Biochemistry Institute, University of Melbourne, Melbourne, VIC 3010, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Franco","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Godbout","sequence":"additional","affiliation":[{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3301-069X","authenticated-orcid":false,"given":"Mohamed","family":"Elbakry","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Biochemistry Section, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Gharbia Governorate, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2812-0060","authenticated-orcid":false,"given":"Rim","family":"Abdelli","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universit\u00e9 Laval, Quebec, QC G1V 0A6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Open Medicine Foundation ME\/CFS Collaborative Center, CHU Sainte-Justine\/Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1C5, Canada"},{"name":"ICanCME Research Network, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Stomatology, Faculty of Dentistry, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Valdez, A.R., Hancock, E.E., Adebayo, S., Kiernicki, D.J., Proskauer, D., Attewell, J.R., Bateman, L., DeMaria, A., Lapp, C.W., and Rowe, P.C. 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