{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T18:31:37Z","timestamp":1780511497587,"version":"3.54.1"},"reference-count":23,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer\u2019s portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n\u2009=\u200912) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n\u2009=\u2009266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n\u2009=\u2009121), and (iv) healthy volunteers (n\u2009=\u200960). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased \u223c30% in HVs administered 100\u2009mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae088","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T16:49:50Z","timestamp":1720802990000},"page":"206-215","source":"Crossref","is-referenced-by-count":8,"title":["Qualified kidney injury biomarkers demonstrate value during early clinical drug development"],"prefix":"10.1093","volume":"201","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8566-5658","authenticated-orcid":false,"given":"Kodihalli C","family":"Ravindra","sequence":"first","affiliation":[{"name":"Department of Drug Safety Research and Development, Pfizer Inc. , Groton, CT 06340,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8797-5577","authenticated-orcid":false,"given":"Kelly A","family":"Fader","sequence":"additional","affiliation":[{"name":"Department of Translational Clinical Sciences, Pfizer Inc. , Groton, CT 06340,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Potter","sequence":"additional","affiliation":[{"name":"Department of Global Biometrics and Data Management, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaher A","family":"Radi","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Research and Development, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary S","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunology, Pfizer Inc. , Collegeville, PA 19426,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karrie A","family":"Brenneman","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Research and Development, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeta B","family":"Amin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunology, Pfizer Inc. , Collegeville, PA 19426,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spencer I","family":"Danto","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunology, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Page","sequence":"additional","affiliation":[{"name":"Department of Translational Clinical Sciences, Pfizer Inc. , Cambridge, MA 02140,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashi K","family":"Ramaiah","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Research and Development, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vishal S","family":"Vaidya","sequence":"additional","affiliation":[{"name":"Department of Drug Safety Research and Development, Pfizer Inc. , Cambridge, MA 02139,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,12]]},"reference":[{"issue":"3","key":"2024092607511053000_kfae088-B1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/ar3256","article-title":"Renal co-morbidity in patients with rheumatic diseases","volume":"13","author":"Anders","year":"2011","journal-title":"Arthritis Res Ther"},{"issue":"5","key":"2024092607511053000_kfae088-B2","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/nbt0510-436","article-title":"Next-generation biomarkers for detecting kidney toxicity","volume":"28","author":"Bonventre","year":"2010","journal-title":"Nat Biotechnol"},{"key":"2024092607511053000_kfae088-B3","author":"C-Path","year":"2019"},{"issue":"10","key":"2024092607511053000_kfae088-B4","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1007\/s00251-004-0743-5","article-title":"The polymorphisms of TIM-1 promoter region are associated with rheumatoid arthritis in a Korean population","volume":"56","author":"Chae","year":"2005","journal-title":"Immunogenetics"},{"issue":"1","key":"2024092607511053000_kfae088-B5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1081\/JDI-120002662","article-title":"Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance","volume":"24","author":"Fujita","year":"2002","journal-title":"Ren Fail"},{"issue":"2","key":"2024092607511053000_kfae088-B6","doi-asserted-by":"crossref","first-page":"193","DOI":"10.2217\/fon.14.166","article-title":"Plasma N-acetyl-glucosaminidase in advanced gastro-intestinal adenocarcinoma correlates with age, stage and outcome","volume":"11","author":"Hartmann","year":"2015","journal-title":"Future Oncol"},{"issue":"8","key":"2024092607511053000_kfae088-B7","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1007\/s00134-015-3934-7","article-title":"Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study","volume":"41","author":"Hoste","year":"2015","journal-title":"Intensive Care Med"},{"issue":"3","key":"2024092607511053000_kfae088-B8","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/emm.1998.24","article-title":"Urinary N-acetyl-beta-D-glucosaminidase in rheumatoid arthritis","volume":"30","author":"Iqbal","year":"1998","journal-title":"Exp Mol Med"},{"issue":"4","key":"2024092607511053000_kfae088-B9","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.ccc.2015.06.005","article-title":"Drug-induced acute kidney injury: a focus on risk assessment for prevention","volume":"31","author":"Kane-Gill","year":"2015","journal-title":"Crit Care Clin"},{"issue":"6","key":"2024092607511053000_kfae088-B10","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1007\/s40620-020-00793-2","article-title":"AKI: an increasingly recognized risk factor for CKD development and progression","volume":"33","author":"Kurzhagen","year":"2020","journal-title":"J Nephrol"},{"issue":"8","key":"2024092607511053000_kfae088-B11","first-page":"e27620","article-title":"An uncommon correlation of rheumatoid arthritis and lupus nephritis: a case report on the unusual progression of lupus nephritis","volume":"14","author":"Lam","year":"2022","journal-title":"Cureus"},{"issue":"9887","key":"2024092607511053000_kfae088-B12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0140-6736(13)60647-9","article-title":"Acute kidney injury: an increasing global concern","volume":"382","author":"Lameire","year":"2013","journal-title":"Lancet"},{"issue":"10","key":"2024092607511053000_kfae088-B13","doi-asserted-by":"crossref","first-page":"e0240942","DOI":"10.1371\/journal.pone.0240942","article-title":"The utility of urinary biomarker panel in predicting renal pathology and treatment response in Chinese lupus nephritis patients","volume":"15","author":"Liu","year":"2020","journal-title":"PLoS One"},{"issue":"4","key":"2024092607511053000_kfae088-B14","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1111\/j.1523-1755.2004.00927.x","article-title":"Spectrum of acute renal failure in the intensive care unit: the Picard experience","volume":"66","author":"Mehta","year":"2004","journal-title":"Kidney Int"},{"issue":"3","key":"2024092607511053000_kfae088-B15","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/ki.2013.374","article-title":"Potential use of biomarkers in acute kidney injury: report and summary of recommendations from the 10th acute dialysis quality initiative consensus conference","volume":"85","author":"Murray","year":"2014","journal-title":"Kidney Int"},{"issue":"10","key":"2024092607511053000_kfae088-B16","doi-asserted-by":"crossref","first-page":"e2019209","DOI":"10.1001\/jamanetworkopen.2020.19209","article-title":"Recommendations on acute kidney injury biomarkers from the acute disease quality initiative consensus conference: a consensus statement","volume":"3","author":"Ostermann","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2024092607511053000_kfae088-B17","doi-asserted-by":"crossref","first-page":"4495","DOI":"10.2147\/IJGM.S361468","article-title":"The predicted value of kidney injury molecule-1 (KIM-1) in healthy people","volume":"15","author":"Peng","year":"2022","journal-title":"Int J Gen Med"},{"issue":"9","key":"2024092607511053000_kfae088-B18","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1515\/cclm-2013-0157","article-title":"Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue?","volume":"51","author":"Pennemans","year":"2013","journal-title":"Clin Chem Lab Med"},{"issue":"8","key":"2024092607511053000_kfae088-B19","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.2215\/CJN.11290821","article-title":"Drug-induced acute kidney injury","volume":"17","author":"Perazella","year":"2022","journal-title":"Clin J Am Soc Nephrol"},{"issue":"6","key":"2024092607511053000_kfae088-B20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1097\/01.ccx.0000184300.68383.95","article-title":"Drug-induced acute kidney injury","volume":"11","author":"Schetz","year":"2005","journal-title":"Curr Opin Crit Care"},{"issue":"6","key":"2024092607511053000_kfae088-B21","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1136\/ard.2009.126532","article-title":"Eular recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs","volume":"69","author":"Smolen","year":"2010","journal-title":"Ann Rheum Dis"},{"key":"2024092607511053000_kfae088-B22","author":"U.S. FDA CDER","year":"2021"},{"issue":"1","key":"2024092607511053000_kfae088-B23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1365-3083.2007.02038.x","article-title":"Expression of human TIM-1 and TIM-3 on lymphocytes from systemic lupus erythematosus patients","volume":"67","author":"Wang","year":"2008","journal-title":"Scand J Immunol"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfae088\/58623986\/kfae088.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/201\/2\/206\/59341901\/kfae088.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/201\/2\/206\/59341901\/kfae088.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T07:51:28Z","timestamp":1727337088000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/201\/2\/206\/7712951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,12]]},"references-count":23,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,7,12]]},"published-print":{"date-parts":[[2024,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfae088","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,10]]},"published":{"date-parts":[[2024,7,12]]}}}