{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:53:52Z","timestamp":1780487632131,"version":"3.54.1"},"reference-count":49,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T00:00:00Z","timestamp":1649030400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,6,2]]},"abstract":"<jats:sec>\n                    <jats:title>OBJECTIVE<\/jats:title>\n                    <jats:p>Understanding mechanisms underlying rapid estimated glomerular filtration rate (eGFR) decline is important to predict and treat kidney disease in type 1 diabetes (T1D).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                    <jats:p>We performed a case-control study nested within four T1D cohorts to identify urinary proteins associated with rapid eGFR decline. Case and control subjects were categorized based on eGFR decline \u22653 and &amp;lt;1 mL\/min\/1.73 m2\/year, respectively. We used targeted liquid chromatography\u2013tandem mass spectrometry to measure 38 peptides from 20 proteins implicated in diabetic kidney disease. Significant proteins were investigated in complementary human cohorts and in mouse proximal tubular epithelial cell cultures.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>The cohort study included 1,270 participants followed a median 8 years. In the discovery set, only cathepsin D peptide and protein were significant on full adjustment for clinical and laboratory variables. In the validation set, associations of cathepsin D with eGFR decline were replicated in minimally adjusted models but lost significance with adjustment for albuminuria. In a meta-analysis with combination of discovery and validation sets, the odds ratio for the association of cathepsin D with rapid eGFR decline was 1.29 per SD (95% CI 1.07\u20131.55). In complementary human cohorts, urine cathepsin D was associated with tubulointerstitial injury and tubulointerstitial cathepsin D expression was associated with increased cortical interstitial fractional volume. In mouse proximal tubular epithelial cell cultures, advanced glycation end product\u2013BSA increased cathepsin D activity and inflammatory and tubular injury markers, which were further increased with cathepsin D siRNA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS<\/jats:title>\n                    <jats:p>Urine cathepsin D is associated with rapid eGFR decline in T1D and reflects kidney tubulointerstitial injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/dc21-2204","type":"journal-article","created":{"date-parts":[[2022,4,4]],"date-time":"2022-04-04T13:08:36Z","timestamp":1649077716000},"page":"1416-1427","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":36,"title":["Urinary Proteomics Identifies Cathepsin D as a Biomarker of Rapid eGFR Decline in Type 1 Diabetes"],"prefix":"10.2337","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9162-7428","authenticated-orcid":false,"given":"Christine P.","family":"Limonte","sequence":"first","affiliation":[{"name":"1Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA"},{"name":"2Kidney Research Institute, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erkka","family":"Valo","sequence":"additional","affiliation":[{"name":"3Folkh\u00e4lsan Institute of Genetics, Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"4Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"5Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viktor","family":"Drel","sequence":"additional","affiliation":[{"name":"6Division of Nephrology, The University of Texas Health Science Center at San Antonio, San Antonio, TX"},{"name":"7Center for Renal Precision Medicine, Division of Nephrology, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-828X","authenticated-orcid":false,"given":"Loki","family":"Natarajan","sequence":"additional","affiliation":[{"name":"8Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health and Moores Cancer Center at UC San Diego Health, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjula","family":"Darshi","sequence":"additional","affiliation":[{"name":"6Division of Nephrology, The University of Texas Health Science Center at San Antonio, San Antonio, TX"},{"name":"7Center for Renal Precision Medicine, Division of Nephrology, Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Forsblom","sequence":"additional","affiliation":[{"name":"3Folkh\u00e4lsan Institute of Genetics, Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"4Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"5Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clark M.","family":"Henderson","sequence":"additional","affiliation":[{"name":"9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew N.","family":"Hoofnagle","sequence":"additional","affiliation":[{"name":"2Kidney Research Institute, University of Washington, Seattle, 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