{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T22:15:04Z","timestamp":1792275304282,"version":"4.4.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T00:00:00Z","timestamp":1731888000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Kidney360"],"published-print":{"date-parts":[[2025,2]]},"abstract":"\n Key Points<\/jats:title>\n \n \n \n Precision medicine trials are feasible in patients with primary glomerular diseases.<\/jats:p>\n <\/jats:list-item>\n \n Patients with FSGS and the best-preserved kidney parenchyma demonstrated the most favorable biomarker response to short-term adalimumab treatment.<\/jats:p>\n <\/jats:list-item>\n \n Targeted therapies for FSGS are more likely to succeed during the course of disease when the injury pathway is activated and can be modified.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>\n \n Background<\/jats:title>\n FSGS and treatment-resistant minimal change disease (TR-MCD) are heterogeneous disorders with subgroups defined by distinct underlying mechanisms of glomerular and tubulointerstitial injury. A noninvasive urinary biomarker profile has been generated to identify patients with intrakidney TNF activation and to predict response to anti-TNF treatment. We conducted this proof-of-concept, multicenter, open-label clinical trial to test the hypothesis that in patients with FSGS or TR-MCD and evidence of intrarenal TNF activation based on their biomarker profile, short-term treatment with adalimumab would reverse the elevated urinary excretion of monocyte chemoattractant protein-1 (MCP-1) and tissue inhibitor of metalloproteinases 1.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Patients with FSGS or TR-MCD, eGFR >30 ml\/min per 1.73 m\n 2<\/jats:sup>\n , urine protein:creatinine ratio \u22651.5 g\/g, and age 6\u201380 years were eligible for this trial. Adalimumab, 20\u201340 mg, was administered through subcutaneous injection every 2 weeks for five doses. Participants were evaluated at weeks 0 (baseline), 2, 8, and 10. Excretion of urinary monocyte chemoattractant protein-1, urinary tissue inhibitor of metalloproteinases 1, urinary excretion of EGF, and plasma monocyte chemoattractant protein-1 were measured at each visit.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Seven participants were enrolled, with median baseline urine protein:creatinine ratio 12.1 mg\/mg (interquartile range [IQR], 2.2\u201318.6), serum albumin 2.4 g\/dl (IQR, 2.0\u20132.8), and eGFR 57 ml\/min per 1.73 m\n 2<\/jats:sup>\n (IQR, 44\u201396). On the basis of self-report, they received all prescribed doses of adalimumab. The patients with the most favorable response on the basis of changes in urinary biomarkers had the best preserved kidney parenchyma based on urinary excretion of EGF.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Precision medicine trials are feasible in rare glomerular disorders. In this pilot study, adalimumab resulted in a heterogenous response of the candidate mechanistic-predictive biomarkers of TNF-mediated inflammation in patients with FSGS or TR-MCD. A reduction was seen in a subgroup of patients with preserved kidney parenchyma. The findings may reflect the challenge to reverse chronic injury at advanced stages of kidney disease or insufficient intrarenal target engagement with the intervention drug dose.<\/jats:p>\n <\/jats:sec>\n \n Clinical Trial registry name and registration number:<\/jats:title>\n NCT04009668.<\/jats:p>\n <\/jats:sec>","DOI":"10.34067\/kid.0000000635","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T15:00:18Z","timestamp":1731942018000},"page":"284-295","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":7,"title":["Precision Medicine Proof-of-Concept Study of a TNF Inhibitor in FSGS and Treatment-Resistant Minimal Change Disease"],"prefix":"10.34067","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7778-292X","authenticated-orcid":false,"given":"Howard","family":"Trachtman","sequence":"first","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4410-2853","authenticated-orcid":false,"given":"Zubin J.","family":"Modi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan"},{"name":"Department of Pediatrics, Susan B. Meister Child Health Evaluation and Research Center, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9136-8454","authenticated-orcid":false,"given":"Wenjun","family":"Ju","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"},{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2443-6638","authenticated-orcid":false,"given":"Edmond","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3360-1886","authenticated-orcid":false,"given":"Silpa","family":"Chinnakotla","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3048-6983","authenticated-orcid":false,"given":"Susan","family":"Massengill","sequence":"additional","affiliation":[{"name":"Atrium Health Levine Children's Hospital, Charlotte, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6780-9168","authenticated-orcid":false,"given":"John","family":"Sedor","sequence":"additional","affiliation":[{"name":"Department of Kidney Medicine, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio"},{"name":"Department of Molecular Medicine, Lerner College of Medicine Case Western University School of Medicine, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-764X","authenticated-orcid":false,"given":"Laura","family":"Mariani","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhai","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5367-1479","authenticated-orcid":false,"given":"Wei","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5866-6644","authenticated-orcid":false,"given":"Hailey","family":"Desmond","sequence":"additional","affiliation":[{"name":"Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8578-3443","authenticated-orcid":false,"given":"Sean","family":"Eddy","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5374-3236","authenticated-orcid":false,"given":"Karthik","family":"Ramani","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6157-6738","authenticated-orcid":false,"given":"Cathie","family":"Spino","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4064-0582","authenticated-orcid":false,"given":"Matthias","family":"Kretzler","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan"},{"name":"Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2024,11,18]]},"reference":[{"issue":"3","key":"B1-20250227","doi-asserted-by":"crossref","first-page":"502","DOI":"10.2215\/CJN.05960616","article-title":"Focal segmental glomerulosclerosis","volume":"12","author":"Rosenberg","year":"2017","journal-title":"Clin J Am Soc Nephrol."},{"issue":"2","key":"B2-20250227","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1053\/j.ackd.2014.01.010","article-title":"Treatment of FSGS in children","volume":"21","author":"Sethna","year":"2014","journal-title":"Adv Chronic Kidney Dis."},{"issue":"9","key":"B3-20250227","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/ndt\/gfab335","article-title":"Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: a prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial","volume":"37","author":"Wheeler","year":"2022","journal-title":"Nephrol Dial Transplant."},{"issue":"3","key":"B4-20250227","doi-asserted-by":"crossref","first-page":"626","DOI":"10.2215\/CJN.05810513","article-title":"Glomerular diseases: FSGS","volume":"9","author":"Bose","year":"2014","journal-title":"Clin J Am Soc Nephrol."},{"issue":"8","key":"B5-20250227","doi-asserted-by":"crossref","first-page":"e2228701","DOI":"10.1001\/jamanetworkopen.2022.28701","article-title":"Comparing kidney Health outcomes in children, adolescents, and adults with focal segmental glomerulosclerosis","volume":"5","author":"Gipson","year":"2022","journal-title":"JAMA Netw Open."},{"issue":"316","key":"B6-20250227","doi-asserted-by":"crossref","first-page":"316ra193","DOI":"10.1126\/scitranslmed.aac7071","article-title":"Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker","volume":"7","author":"Ju","year":"2015","journal-title":"Sci Transl Med."},{"issue":"11","key":"B7-20250227","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41581-020-0286-5","article-title":"Integrated multi-omics approaches to improve classification of chronic kidney disease","volume":"16","author":"Eddy","year":"2020","journal-title":"Nat Rev Nephrol."},{"issue":"4","key":"B8-20250227","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/ki.2012.428","article-title":"Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach","volume":"83","author":"Gadegbeku","year":"2013","journal-title":"Kidney Int."},{"issue":"2","key":"B9-20250227","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.kint.2023.11.018","article-title":"Rationale and design of the Nephrotic Syndrome Study Network (NEPTUNE) Match in glomerular diseases: designing the right trial for the right patient, today","volume":"105","author":"Trachtman","year":"2024","journal-title":"Kidney Int."},{"issue":"3","key":"B10-20250227","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.kint.2022.10.023","article-title":"Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis","volume":"103","author":"Mariani","year":"2023","journal-title":"Kidney Int."},{"issue":"4","key":"B11-20250227","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.kint.2018.05.022","article-title":"JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis","volume":"94","author":"Tao","year":"2018","journal-title":"Kidney Int."},{"issue":"1","key":"B12-20250227","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1053\/j.ajkd.2009.08.019","article-title":"Phase 1 trial of adalimumab in focal segmental glomerulosclerosis (FSGS): II. Report of the FONT (novel therapies for resistant FSGS) study group","volume":"55","author":"Joy","year":"2010","journal-title":"Am J Kidney Dis."},{"issue":"16","key":"B13-20250227","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12882-015-0094-5","article-title":"Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group","volume":"16","author":"Trachtman","year":"2015","journal-title":"BMC Nephrol."},{"issue":"3","key":"B14-20250227","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1681\/ASN.2008030287","article-title":"New equations to estimate GFR in children with CKD","volume":"20","author":"Schwartz","year":"2009","journal-title":"J Am Soc Nephrol."},{"issue":"9","key":"B15-20250227","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","article-title":"A new equation to estimate glomerular filtration rate","volume":"150","author":"Levey","year":"2009","journal-title":"Ann Intern Med."},{"issue":"3","key":"B16-20250227","doi-asserted-by":"crossref","first-page":"414","DOI":"10.2215\/CJN.04780517","article-title":"An outcomes-based definition of proteinuria remission in focal segmental glomerulosclerosis","volume":"13","author":"Troost","year":"2018","journal-title":"Clin J Am Soc Nephrol."},{"issue":"4","key":"B17-20250227","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.xkme.2021.01.013","article-title":"Health-related quality of Life in focal segmental glomerular sclerosis and minimal change disease: a qualitative study of children and adults to inform patient-reported outcomes","volume":"3","author":"Carlozzi","year":"2021","journal-title":"Kidney Med."},{"issue":"9","key":"B18-20250227","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1002\/jcph.121","article-title":"Contribution of renal and non-renal clearance on increased total clearance of adalimumab in glomerular disease","volume":"53","author":"Roberts","year":"2013","journal-title":"J Clin Pharmacol."},{"issue":"5","key":"B19-20250227","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1111\/j.1523-1755.2005.00664.x","article-title":"Renal macrophage activation and Th2 polarization precedes the development of nephrotic syndrome in Buffalo\/Mna rats","volume":"68","author":"LeBerre","year":"2005","journal-title":"Kidney Int."},{"issue":"3","key":"B20-20250227","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0272-6386(12)80742-6","article-title":"Elevated levels of tumor necrosis factor-\u03b1 in the nephrotic syndrome in humans","volume":"21","author":"Suranyi","year":"1993","journal-title":"Am J Kidney Dis."},{"issue":"5","key":"B21-20250227","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1053\/ajkd.2002.32769","article-title":"T-lymphocyte populations and cytokines in childhood nephrotic syndrome","volume":"39","author":"Lama","year":"2002","journal-title":"Am J Kidney Dis."},{"issue":"6","key":"B22-20250227","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1007\/s00467-003-1122-4","article-title":"Tumor necrosis factor-\u03b1 production from mononuclear cells in nephrotic syndrome","volume":"18","author":"Bakr","year":"2003","journal-title":"Pedimat Nephrol."},{"issue":"3","key":"B23-20250227","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1681\/ASN.V93433","article-title":"TNF-\u03b1 increases albumin permeability of isolated rat glomeruli through the generation of superoxide","volume":"9","author":"McCarthy","year":"1998","journal-title":"J Am Soc Nephrol."},{"issue":"9","key":"B24-20250227","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1172\/JCI85939","article-title":"Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury","volume":"126","author":"Pedigo","year":"2016","journal-title":"J Clin Invest."},{"key":"B25-20250227","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.molimm.2017.01.009","article-title":"Tumor necrosis factor-alpha inhibitors suppress CCL2 chemokine in monocytes via epigenetic modification","volume":"83","author":"Lin","year":"2017","journal-title":"Mol Immunol."},{"key":"B26-20250227","doi-asserted-by":"crossref","first-page":"112653","DOI":"10.1016\/j.biopha.2022.112653","article-title":"Transcriptional regulation of chemokine network by biologic monotherapy in ileum of patients with Crohn's disease","volume":"147","author":"Linares","year":"2022","journal-title":"Biomed Pharmacother."},{"issue":"1","key":"B27-20250227","doi-asserted-by":"crossref","first-page":"4903","DOI":"10.1038\/s41467-023-39740-7","article-title":"An integrated organoid omics map extends modeling potential of kidney disease","volume":"14","author":"Lass\u00e9","year":"2023","journal-title":"Nat Commun."},{"issue":"6","key":"B28-20250227","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1080\/10543406.2020.1818251","article-title":"Continual reassessment method with regularization in phase I clinical trials","volume":"30","author":"Li","year":"2020","journal-title":"J Biopharm Stat."},{"issue":"4","key":"B29-20250227","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1111\/biom.13217","article-title":"PA-CRM: a continuous reassessment method for pediatric phase I oncology trials with concurrent adult trials","volume":"76","author":"Li","year":"2020","journal-title":"Biometrics."}],"container-title":["Kidney360"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000000635","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T20:02:59Z","timestamp":1786478579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.34067\/KID.0000000635"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,18]]},"references-count":29,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025]]}},"URL":"https:\/\/doi.org\/10.34067\/kid.0000000635","relation":{},"ISSN":["2641-7650"],"issn-type":[{"value":"2641-7650","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,18]]},"assertion":[{"value":"2024-04-16","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-04","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}