{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:01:53Z","timestamp":1790776913669,"version":"4.1.0"},"reference-count":20,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100015303","name":"Otsuka Pharmaceutical Development and Commercialization","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015303","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Nephrology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>Tolvaptan delays growth in total kidney volume (TKV) and decline in estimated glomerular filtration rate (eGFR) among individuals with autosomal dominant polycystic kidney disease (ADPKD) at elevated risk of rapid progression. We evaluated changes in urine osmolality (Uosm) after treatment initiation as a potential biomarker of long\u2010term response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This was a post hoc analysis of TEMPO 3:4, a 3\u2010year, randomized, placebo\u2010controlled trial of tolvaptan. Causal mediation analysis assessed if the effect of tolvaptan on longer\u2010term outcomes of change in eGFR and TKV at month 36 was mediated by change in Uosm at week 3. Analyses were performed separately for non\u2010Japanese and Japanese participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The average causal mediation effect (ACME) of change in Uosm on eGFR at month 36 was statistically significant (2.4; 95% quasi\u2010Bayesian confidence interval [CI] 1.2, 3.6) in the non\u2010Japanese cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009948). In the Japanese cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009138), whereas the ACME for change in Uosm was non\u2010significant (\u22120.3 [95% CI: \u22122.3, 1.7]), the average direct effect (ADE) of tolvaptan on eGFR was statistically significant (8.4 [95% CI 3.1, 12.4]). For percentage change in TKV, the ADE of tolvaptan was statistically significant in both the non\u2010Japanese (\u22128.3 [95% CI: \u221210.5, \u22126.3]) and Japanese cohorts (\u221212.0 [95% CI: \u221217.4, \u22127.5]).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study supported short\u2010term change in Uosm as a predictive biomarker of longer\u2010term kidney function in a non\u2010Japanese cohort; the relationship was not significant in the smaller Japanese cohort. Tolvaptan exhibited a direct treatment effect on the growth of kidney volume in both cohorts of ADPKD patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nep.70292","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:44:37Z","timestamp":1790775877000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mediation Analysis of Urine Osmolality and Response to Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Assessment"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4936-4852","authenticated-orcid":false,"given":"Ryo","family":"Matsuura","sequence":"first","affiliation":[{"name":"Department of Nephrology and Endocrinology, Graduate School of Internal Medicine The University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent","family":"Doi","sequence":"additional","affiliation":[{"name":"Department of Emergency and Critical Care Medicine The University of Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development and Commercialization, Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Maringer","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development and Commercialization, Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1957-273X","authenticated-orcid":false,"given":"Sachin","family":"Hajarnis","sequence":"additional","affiliation":[{"name":"Otsuka Pharmaceutical Development and Commercialization, Inc.  Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1874-1846","authenticated-orcid":false,"given":"Yoshifumi","family":"Hamasaki","sequence":"additional","affiliation":[{"name":"Department of Haemodialysis and Apheresis The University of Tokyo Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2012070650"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen\u20102019\u2010034103"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010012\u20100611\u20109"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010018\u20101617\u20108"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12372"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010021\u201002068\u2010x"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010015\u20101086\u20102"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010021\u201002083\u2010y"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1205511"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1710030"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.34067\/kid.0000000000000485"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1681\/asn.2013101037"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.119"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0020761"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2021.11.034"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfx043"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.2215\/cjn.06300615"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa054341"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2018.12.023"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfaf048"}],"container-title":["Nephrology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/nep.70292","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/nep.70292","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/nep.70292","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:44:38Z","timestamp":1790775878000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/nep.70292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":20,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/nep.70292"],"URL":"https:\/\/doi.org\/10.1111\/nep.70292","archive":["Portico"],"relation":{},"ISSN":["1320-5358","1440-1797"],"issn-type":[{"value":"1320-5358","type":"print"},{"value":"1440-1797","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"assertion":[{"value":"2026-05-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70292"}}