{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:58:58Z","timestamp":1790841538994,"version":"4.1.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"KAKENHI","doi-asserted-by":"publisher","award":["23K07698"],"award-info":[{"award-number":["23K07698"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Welfare Sciences Research","award":["23FC1047"],"award-info":[{"award-number":["23FC1047"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["24015773"],"award-info":[{"award-number":["24015773"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["22810094"],"award-info":[{"award-number":["22810094"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["23ek0109617s1702"],"award-info":[{"award-number":["23ek0109617s1702"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP256f0137011"],"award-info":[{"award-number":["JP256f0137011"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health, Labor, and Welfare Sciences Research Grants","award":["23FC1047"],"award-info":[{"award-number":["23FC1047"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Heterozygous pathogenic variants in COL4A3 or COL4A4 are relatively common and associated with a broad clinical spectrum. However, nomenclature and risk stratification remain unsettled. We aimed to investigate temporal diagnostic trends and clinical features of haematuria-positive individuals with heterozygous COL4A3\/COL4A4 variants in a genetic testing cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective cohort study involved 992 families genetically diagnosed with Alport syndrome at a single centre in Japan between 2006 and 2023. We identified 265 families comprising 299 haematuria-positive individuals with heterozygous pathogenic or likely pathogenic COL4A3\/COL4A4 variants. For kidney failure (KF) analysis, 627 individuals, including affected relatives, were evaluated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>At the family level, the proportion of the study group increased from 8.4% of genetically diagnosed Alport syndrome cases during the Sanger sequencing era (2006\u20132015) to 26.6% during early next-generation sequencing implementation (2015\u20132019), and 39.1% in the recent period (2020\u20132023). At genetic diagnosis, 75.3% of individuals had proteinuria and 4.7% had KF. Kaplan\u2013Meier analysis showed that the median ages at first detection of haematuria and proteinuria, and at onset of KF, were 10, 26, and 72 years, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Individuals with haematuria and heterozygous COL4A3\/COL4A4 variants accounted for an increasing proportion of genetically diagnosed cases of Alport syndrome. Although this referred cohort does not represent all individuals with heterozygous COL4A3\/COL4A4 variants, our findings delineate the natural history of haematuria-positive individuals with these variants and may support early diagnosis and risk stratification aimed at preventing progression to KF.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ckj\/sfag301","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:47:27Z","timestamp":1788353247000},"source":"Crossref","is-referenced-by-count":0,"title":["Heterozygous COL4A3\/COL4A4 variants: diagnostic trends and clinical kidney outcomes"],"prefix":"10.1093","volume":"19","author":[{"given":"Yu","family":"Tanaka","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1655-6030","authenticated-orcid":false,"given":"Tomoko","family":"Horinouchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Inoki","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chika","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideaki","family":"Kitakado","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8387-8008","authenticated-orcid":false,"given":"Nana","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4946-1345","authenticated-orcid":false,"given":"China","family":"Nagano","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiko","family":"Yamamura","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Ishimori","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0290-3137","authenticated-orcid":false,"given":"Kandai","family":"Nozu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Kobe University Graduate School of Medicine , Hyogo ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"2026100103173288600_bib1","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1007\/s10157-018-1629-4","article-title":"A review of clinical characteristics and genetic backgrounds in Alport syndrome","volume":"23","author":"Nozu","year":"2019","journal-title":"Clin Exp Nephrol"},{"key":"2026100103173288600_bib2","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/0002-9343(81)90571-4","article-title":"Alport\u2019s syndrome. 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