{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:30:38Z","timestamp":1786116638606,"version":"build-2736575974"},"reference-count":22,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"abstract":"<jats:p>\n                    Uromodulin (UMOD) regulates tubular sodium handling and modulates NKCC2, the molecular target of loop diuretics (LD). Although\n                    <jats:italic>UMOD variants<\/jats:italic>\n                    have been associated with blood pressure and hypertension, their pharmacogenetic relevance in heart failure (HF) remains unknown. We assessed whether the\n                    <jats:italic>UMOD rs13333226<\/jats:italic>\n                    genotype is associated with clinical outcomes among patients with HF who initiated LD. We assembled a cohort of UK biobank (UKB) participants diagnosed with HF who initiated LD. Patients were followed in an intention\u2010to\u2010treat fashion for up to 12\u2009months. Cox models estimated confounder\u2010adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) comparing\n                    <jats:italic>rs13333226\u2010AA<\/jats:italic>\n                    versus\n                    <jats:italic>rs13333226\u2010AG\/GG<\/jats:italic>\n                    genotypes. The primary effectiveness outcome was worsening HF, defined as hospitalization for HF or death with HF as the primary cause. Additional effectiveness and safety outcomes were major adverse cardiovascular events (MACE), acute kidney injury (AKI), and all\u2010cause mortality. Secondary analyses stratified by age and sex. Sensitivity analyses restricted follow\u2010up to 3 and 6\u2009months. Among 1,426 HF patients initiating LD (92% furosemide, mean age 68\u2009years, 34% female), the\n                    <jats:italic>rs13333226\u2010AA<\/jats:italic>\n                    genotype was not associated with worsening HF (HR, 0.95; 95% CI, 0.76\u20131.20), MACE (HR, 0.97; 95% CI, 0.62\u20131.52), AKI (HR, 1.05; 95% CI, 0.68\u20131.64), or all\u2010cause mortality (HR, 1.17; 95% CI, 0.76\u20131.78). There was no effect modification by demographics. Shorter follow\u2010up periods did not affect the results. In HF patients initiating LD,\n                    <jats:italic>UMOD<\/jats:italic>\n                    rs13333226 was not associated with effectiveness or safety outcomes. These findings do not support a clinically meaningful pharmacogenetic role for this variant.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70426","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:39:47Z","timestamp":1786016387000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>\n                      <i>UMOD<\/i>\n                    <\/scp>\n                    Genotype and Clinical Outcomes in Heart Failure Patients Treated with Loop Diuretics: A\n                    <scp>UK<\/scp>\n                    Biobank Pharmacogenetic Cohort Study"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4818-211X","authenticated-orcid":false,"given":"Reinhold","family":"Kreutz","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5946-7137","authenticated-orcid":false,"given":"Pimrapat","family":"Gebert","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"},{"name":"Institute of Biometry and Clinical Epidemiology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7387-8899","authenticated-orcid":false,"given":"Jingwen","family":"Luo","sequence":"additional","affiliation":[{"name":"Institute of Biometry and Clinical Epidemiology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8511-5340","authenticated-orcid":false,"given":"Paraskevi","family":"Tassopoulou","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0812-8549","authenticated-orcid":false,"given":"Juliane","family":"Bolbrinker","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6005-4006","authenticated-orcid":false,"given":"Antonios","family":"Douros","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology and Toxicology, Charit\u00e9 \u2010 Universit\u00e4tsmedizin Berlin  Berlin Germany"},{"name":"School of Epidemiology and Public Health, University of Ottawa  Ottawa Ontario Canada"},{"name":"Department of Epidemiology Biostatistics and Occupational Health, McGill University  Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.1093\/eurheartj\/ehad195","article-title":"2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"44","author":"McDonagh T.A.","year":"2023","journal-title":"Eur. Heart J."},{"key":"e_1_2_11_2_1","first-page":"e876","article-title":"2022 AHA\/ACC\/HFSA guideline for the Management of Heart Failure","volume":"145","author":"Heidenreich P.A.","year":"2022","journal-title":"Circulation"},{"key":"e_1_2_11_3_1","first-page":"1178","article-title":"Diuretic therapy for patients with heart failure: JACC state\u2010of\u2010the\u2010art review","volume":"75","author":"Felker G.M.","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"e_1_2_11_4_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1007\/s11897-024-00643-3","article-title":"Diuretic treatment in patients with heart failure: current evidence and future directions \u2010 part I: loop diuretics","volume":"21","author":"Cuthbert J.J.","year":"2024","journal-title":"Curr. Heart Fail. Rep."},{"key":"e_1_2_11_5_1","article-title":"Blood pressure\u2010lowering efficacy of loop diuretics for primary hypertension","volume":"2015","author":"Musini V.M.","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"e_1_2_11_6_1","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1093\/eurheartj\/ehu065","article-title":"Diuretic response in acute heart failure: clinical characteristics and prognostic significance","volume":"35","author":"Valente M.A.","year":"2014","journal-title":"Eur. Heart J."},{"key":"e_1_2_11_7_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1161\/CIRCHEARTFAILURE.113.000895","article-title":"Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure","volume":"7","author":"Testani J.M.","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"e_1_2_11_8_1","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1161\/HYPERTENSIONAHA.124.23122","article-title":"UMOD genotype\u2010blinded trial of ambulatory blood pressure response to Torasemide","volume":"81","author":"McCallum L.","year":"2024","journal-title":"Hypertension"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1038\/nm.3384","article-title":"Common noncoding UMOD gene variants induce salt\u2010sensitive hypertension and kidney damage by increasing uromodulin expression","volume":"19","author":"Trudu M.","year":"2013","journal-title":"Nat. Med."},{"key":"e_1_2_11_10_1","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nrneph.2017.101","article-title":"Uromodulin: from physiology to rare and complex kidney disorders","volume":"13","author":"Devuyst O.","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"e_1_2_11_11_1","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s11906-024-01317-0","article-title":"Insights into uromodulin and blood pressure","volume":"26","author":"Zhou M.","year":"2024","journal-title":"Curr. Hypertens. Rep."},{"key":"e_1_2_11_12_1","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1093\/eurheartj\/ehae178","article-title":"2024 ESC guidelines for the management of elevated blood pressure and hypertension","volume":"45","author":"McEvoy J.W.","year":"2024","journal-title":"Eur. Heart J."},{"key":"e_1_2_11_13_1","doi-asserted-by":"crossref","first-page":"e114","DOI":"10.1161\/CIR.0000000000001396","article-title":"2025 AHA\/ACC\/AANP\/AAPA\/ABC\/ACCP\/ACPM\/AGS\/AMA\/ASPC\/NMA\/PCNA\/SGIM guideline for the prevention, detection, evaluation and Management of High Blood Pressure in adults","volume":"152","author":"Jones D.W.","year":"2025","journal-title":"Circulation"},{"key":"e_1_2_11_14_1","first-page":"1874","article-title":"2023 ESH guidelines for the management of arterial hypertension","volume":"41","author":"Mancia G.","year":"2023","journal-title":"J. Hypertens."},{"key":"e_1_2_11_15_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jacc.2021.03.342","article-title":"United Kingdom biobank (UK biobank): JACC focus seminar 6\/8","volume":"78","author":"Caleyachetty R.","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1093\/ehjcvp\/pvaf067","article-title":"Diuretic strategies in acute heart failure: a systematic review and network meta\u2010analysis of randomized clinical trials","volume":"12","author":"Cannat\u00e0 A.","year":"2026","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"e_1_2_11_17_1","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrcardio.2015.14","article-title":"The vulnerable phase after hospitalization for heart failure","volume":"12","author":"Greene S.J.","year":"2015","journal-title":"Nat. Rev. Cardiol."},{"key":"e_1_2_11_18_1","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.amjcard.2022.08.035","article-title":"Impact of worsening heart failure on long\u2010term prognosis in patients with heart failure with reduced ejection fraction","volume":"184","author":"Chimed S.","year":"2022","journal-title":"Am. J. Cardiol."},{"key":"e_1_2_11_19_1","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1001\/jamacardio.2024.2969","article-title":"Hospital heart failure medical therapy score and associated clinical outcomes and costs","volume":"9","author":"Polsinelli V.B.","year":"2024","journal-title":"JAMA Cardiol."},{"key":"e_1_2_11_20_1","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1002\/pds.4197","article-title":"Bias from depletion of susceptibles: the example of hormone replacement therapy and the risk of venous thromboembolism","volume":"26","author":"Renoux C.","year":"2017","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"e_1_2_11_21_1","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S1388-9842(02)00122-8","article-title":"Torasemide in chronic heart failure: results of the TORIC study","volume":"4","author":"Cos\u00edn J.","year":"2002","journal-title":"Eur. J. Heart Fail."},{"key":"e_1_2_11_22_1","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1001\/jama.2022.23924","article-title":"Effect of Torsemide vs furosemide after discharge on all\u2010cause mortality in patients hospitalized with heart failure: the TRANSFORM\u2010HF randomized clinical trial","volume":"329","author":"Mentz R.J.","year":"2023","journal-title":"JAMA"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70426","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70426","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70426","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T11:39:51Z","timestamp":1786016391000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":22,"alternative-id":["10.1002\/cpt.70426"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70426","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,6]]},"assertion":[{"value":"2026-04-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cpt.70426"}}