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In this study, we systematically evaluated 3 reference tissue types \u2014 tumor nephrectomy (TN), pretransplant biopsies from living donors (LD), and percutaneous biopsies from healthy control volunteers (HC) \u2014 to determine their impact on differential gene expression across 3 diabetic kidney disease states. We observed distinct injury markers, cell state proportions, and gene signatures associated with procurement method, sex, and donor age. Adjustment for these confounding factors significantly influenced pathway analysis results. Specifically, correcting for age and sex eliminated significant enrichment of IFN-\u03b3 response when comparing the diabetes mellitus\u2013resilient group and HC group. Processes related to biological aging were enriched in older reference tissues, potentially confounding disease-specific interpretations. Importantly, TNF signaling via NF-\u03baB remained enriched in LD and TN samples relative to HC, even after accounting for confounders. These results underscore the critical importance of selecting appropriate control tissues and rigorously adjusting for confounding variables to reliably discern the molecular mechanisms underlying kidney diseases.<\/jats:p>","DOI":"10.1172\/jci.insight.204385","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T18:35:12Z","timestamp":1779302112000},"source":"Crossref","is-referenced-by-count":0,"title":["Not all reference samples are equal in single-cell transcriptomics of human kidney tissue"],"prefix":"10.1172","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6280-9639","authenticated-orcid":true,"given":"Rajasree","family":"Menon","sequence":"first","affiliation":[{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul L.","family":"Kimmel","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-9973","authenticated-orcid":true,"given":"Edgar A.","family":"Otto","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lalita","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Godfrey","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadhl","family":"Alakwaa","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3539-1075","authenticated-orcid":true,"given":"Celine C.","family":"Berthier","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minnie M.","family":"Sarwal","sequence":"additional","affiliation":[{"name":"Division of Transplant Surgery, Department of Surgery, School of Medicine, University of California, San Francisco, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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