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To quantitatively assess spatial injury patterns, we collected high dimensional spatial proteomics data from 23 LuN, 33 RAR, and 8 kidney control (KC) biopsies. We developed a computational pipeline to segment and classify tubules, capillaries, and glomeruli in whole-slide images using three trained neural networks (Renal Damage diagnosis, RDDx). RDDx achieved high accuracy and generalizability, reliably identifying small capillaries and differentiating tubular and vascular inflammation in kidney tissues. Both LuN and RAR showed reduced tubular and capillary areas with expanded interstitial space. LuN displayed patchy clusters of stressed and inflamed tubules, whereas RAR exhibited diffuse injury. Within RAR, T cell\u2013mediated rejection (TCMR) showed intense tubulitis while antibody-mediated rejection (ABMR) featured proliferating and inflamed capillaries near atrophic tubules. RDDx quantitative metric outputs correlated with histopathological scores, highlighting their reproducibility and clinical relevance. Stressed tubules in mildly inflamed LuN biopsies suggested they were a sensitive injury marker, while proliferating capillaries revealed microvascular remodeling in ABMR. These findings indicated RDDx can identify and quantify damage mechanisms specific to each renal disease thus facilitating future mechanistic studies and therapeutic target discovery.<\/jats:p>","DOI":"10.64898\/2026.01.14.699505","type":"posted-content","created":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:35:12Z","timestamp":1768509312000},"source":"Crossref","is-referenced-by-count":2,"title":["High-dimensional spatial proteomics and novel machine learning pipeline identifies disease specific renal damage states"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4172-9590","authenticated-orcid":false,"given":"Thao","family":"Cao","sequence":"first","affiliation":[{"name":"Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA"},{"name":"Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0543-074X","authenticated-orcid":false,"given":"Madeleine S.","family":"Torcasso","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA"},{"name":"Department of Medicine, Section of Hematology\/Oncology, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junting","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3640-4133","authenticated-orcid":false,"given":"Satoshi","family":"Hara","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA"},{"name":"Department of Nephrology and Rheumatology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1404-3015","authenticated-orcid":false,"given":"Michael S.","family":"Andrade","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6877-5510","authenticated-orcid":false,"given":"Anthony","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Casella","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA"},{"name":"Department of Radiology and Committee on Medical Physics, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0460-0196","authenticated-orcid":false,"given":"Anita S.","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5482-9728","authenticated-orcid":false,"given":"Maryellen L.","family":"Giger","sequence":"additional","affiliation":[{"name":"Department of Radiology and Committee on Medical Physics, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus R.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020606245313000_2026.01.14.699505v1.1","unstructured":"StatPearls. 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