{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T16:29:14Z","timestamp":1788193754300,"version":"build-2803163510"},"reference-count":30,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002997","name":"Nierstichting","doi-asserted-by":"publisher","award":["170KG20"],"award-info":[{"award-number":["170KG20"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002997","name":"Nierstichting","doi-asserted-by":"publisher","award":["CP1805"],"award-info":[{"award-number":["CP1805"]}],"id":[{"id":"10.13039\/501100002997","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Karyomegalic interstitial nephropathy (KIN) has been reported as an incidental finding in patients with childhood cancer treated with ifosfamide. It is defined by the presence of tubular epithelial cells (TECs) with enlarged, irregular, and hyperchromatic nuclei. Cellular senescence has been proposed to be involved in kidney fibrosis in hereditary KIN patients. We report that KIN could be diagnosed 7\u201332\u2009months after childhood cancer diagnosis in 6\/6 consecutive patients biopsied for progressive chronic kidney disease (CKD) of unknown cause between 2018 and 2021. The morphometry of nuclear size distribution and markers for DNA damage (\u03b3H2AX), cell\u2010cycle arrest (p21+, Ki67\u2212), and nuclear lamina decay (loss of lamin B1), identified karyomegaly and senescence features in TECs. Polyploidy was assessed by chromosome fluorescence\n                    <jats:italic>in situ<\/jats:italic>\n                    hybridization (FISH). In all six patients the number of p21\u2010positive TECs far exceeded the typically small numbers of truly karyomegalic cells, and p21\u2010positive TECs contained less lysozyme, testifying to defective resorption, which explains the consistently observed low\u2010molecular\u2010weight (LMW) proteinuria. In addition, polyploidy of TEC was observed to correlate with loss of lysozyme staining. Importantly, in the five patients with the largest nuclei, the percentage of p21\u2010positive TECs tightly correlated with estimated glomerular filtration rate loss between biopsy and last follow\u2010up (\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u20090.93,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). We conclude that cellular senescence is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with KIN and appears to be a prevalent cause of otherwise unexplained CKD and LMW proteinuria in children treated with DNA\u2010damaging and cell stress\u2010inducing therapy including ifosfamide. \u00a9 2023 The Authors.\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6202","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T13:00:31Z","timestamp":1696424431000},"page":"455-464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cellular senescence in kidney biopsies is associated with tubular dysfunction and predicts\n                    <scp>CKD<\/scp>\n                    progression in childhood cancer patients with karyomegalic interstitial nephropathy"],"prefix":"10.1002","volume":"261","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4543-9792","authenticated-orcid":false,"given":"Sebastiaan N","family":"Knoppert","sequence":"first","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy G","family":"Keijzer\u2010Veen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Wilhelmina Children's Hospital  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris A","family":"Valentijn","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marry M","family":"van den Heuvel\u2010Eibrink","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc R","family":"Lilien","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Wilhelmina Children's Hospital  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology Wilhelmina Children's Hospital  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianne M","family":"Haveman","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijn F","family":"Stokman","sequence":"additional","affiliation":[{"name":"Department of Genetics University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert O","family":"Janssens","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology  Utrecht The Netherlands"},{"name":"Department of Radiation Oncology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"van Kempen","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel","family":"Broekhuizen","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel","family":"Goldschmeding","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6475-0706","authenticated-orcid":false,"given":"Tri Q","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Pathology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00467-011-1815-z"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711130303"},{"key":"e_1_2_8_4_1","first-page":"54","article-title":"Systemic karyomegaly associated with chronic interstitial nephritis. A new disease entity?","volume":"12","author":"Mihatsch MJ","year":"1979","journal-title":"Clin Nephrol"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2347"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(96)90047-5"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13039-019-0442-4"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/17.11.1914"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00770"},{"key":"e_1_2_8_11_1","first-page":"305","article-title":"Gamma\u2010H2AX \u2013 a novel biomarker for DNA double\u2010strand breaks","volume":"22","author":"Kuo LJ","year":"2008","journal-title":"In Vivo"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03753-4"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33110-5"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.4103\/0971-4065.171233"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13730-014-0124-3"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.20858"},{"key":"e_1_2_8_17_1","first-page":"1636","article-title":"Risk factors for nephrotoxicity after ifosfamide treatment in children: a UKCCSG late effects group study. United Kingdom Children's cancer study group","volume":"82","author":"Skinner R","year":"2000","journal-title":"Br J Cancer"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1177\/009127009903900504"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.22364"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-022-00631-7"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.4103\/0971-4065.127905"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.02.001"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2018121251"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3960"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602554"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.17327"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2019.02.006"},{"key":"e_1_2_8_28_1","first-page":"CD008944","article-title":"Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer","volume":"3","author":"Kooijmans EC","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020071002"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020060849"},{"key":"e_1_2_8_31_1","first-page":"1","article-title":"Kidney disease: improving global outcomes (KDIGO) CKD work group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease","volume":"3","author":"Levin A","year":"2013","journal-title":"Kidney Int Suppl"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.6202","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T11:05:57Z","timestamp":1761044757000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.6202"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,4]]},"references-count":30,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1002\/path.6202"],"URL":"https:\/\/doi.org\/10.1002\/path.6202","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,4]]},"assertion":[{"value":"2022-11-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}