{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T05:05:08Z","timestamp":1793855108181,"version":"4.6.1"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["952512"],"award-info":[{"award-number":["952512"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018718","name":"KUTTAM","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018718","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Interleukin (IL)-6 is a major pro-inflammatory cytokine and central regulator of innate and adaptive immune responses. Clinical trials testing antibodies against IL-6 or its receptors have demonstrated its involvement in the pathogenesis of several autoimmune and inflammatory disorders and in the systemic inflammation and anemia associated to kidney failure and also in kidney allograft rejection. Additionally, the anti-IL-6 receptor antibody tocilizumab and the anti-IL-6 antibody clazakizumab have been studied for the treatment of na\u00efve as well as resistant antibody-mediated kidney allograft rejection with mixed results in observational studies and early clinical development. Following promising results with a clazakizumab in a phase 2 placebo-controlled trial, a large phase 3 trial (IMAGINE) was terminated in 2024 for futility at interim analysis. Investigator-initiated clinical development continues in a smaller phase 3 trial testing tocilizumab (INTERCEPT). In this viewpoint article, we evaluate the pathophysiology of IL-6 in antibody-mediated kidney allograft rejection along with the current status of the clinical development of IL-6 targeting therapies for antibody-mediated kidney allograft rejection episodes within the wider frame of IL-6 targeting therapies in kidney failure that are considered the major causes of graft loss in kidney transplantation.<\/jats:p>","DOI":"10.1093\/ckj\/sfaf108","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T07:33:19Z","timestamp":1744615999000},"source":"Crossref","is-referenced-by-count":11,"title":["Targeting IL-6 in antibody-mediated kidney transplant rejection"],"prefix":"10.1093","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-0675","authenticated-orcid":false,"given":"Mehmet","family":"Kanbay","sequence":"first","affiliation":[{"name":"Division of Nephrology, Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berk","family":"Mizrak","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sidar","family":"Copur","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Internal Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezgi N","family":"Alper","sequence":"additional","affiliation":[{"name":"Koc University School of Medicine Department of Medicine, , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebahat","family":"Akgul","sequence":"additional","affiliation":[{"name":"Transplant Immunology Research Center of Excellence TIREX, Ko\u00e7 University Hospital , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9805-9523","authenticated-orcid":false,"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Universidad Autonoma de Madrid and IIS-Fundacion Jimenez Diaz Department of Medicine, , Madrid ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caner","family":"Susal","sequence":"additional","affiliation":[{"name":"Transplant Immunology Research Center of Excellence TIREX, Ko\u00e7 University Hospital , Istanbul ,","place":["Turkey"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"2025051205270935600_bib1","doi-asserted-by":"publisher","first-page":"sfae053","DOI":"10.1093\/ckj\/sfae053","article-title":"Decreased life expectancy: a health outcome not corrected by kidney replacement therapy that emphasizes the need for primary prevention of CKD","volume":"17","author":"Cordero","year":"2024","journal-title":"Clin Kidney J"},{"key":"2025051205270935600_bib2","doi-asserted-by":"publisher","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in inflammation, immunity, and disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2025051205270935600_bib3","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s40472-021-00331-4","article-title":"IL-6 directed therapy in transplantation","volume":"8","author":"Miller","year":"2021","journal-title":"Curr Transplant Rep"},{"key":"2025051205270935600_bib4","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1080\/17512433.2022.2097905","article-title":"Current status and prospects of IL-6-targeting therapy","volume":"15","author":"Narazaki","year":"2022","journal-title":"Expert Rev Clin Pharmacol"},{"key":"2025051205270935600_bib5","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1186\/s12348-019-0182-y","article-title":"Interleukin-6 inhibition in the management of non-infectious uveitis and beyond","volume":"9","author":"Karkhur","year":"2019","journal-title":"J Ophthalmic Inflamm Infect"},{"key":"2025051205270935600_bib6","doi-asserted-by":"publisher","first-page":"2060","DOI":"10.1016\/S0140-6736(21)00520-1","article-title":"IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial","volume":"397","author":"Ridker","year":"2021","journal-title":"Lancet"},{"key":"2025051205270935600_bib7","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1038\/s41591-024-03043-1","article-title":"IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial","volume":"30","author":"Chertow","year":"2024","journal-title":"Nat Med"},{"key":"2025051205270935600_bib8","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1111\/tri.13436","article-title":"The therapeutic challenge of late antibody-mediated kidney allograft rejection","volume":"32","author":"B\u00f6hmig","year":"2019","journal-title":"Transpl Int"},{"key":"2025051205270935600_bib9","doi-asserted-by":"publisher","first-page":"911","DOI":"10.1097\/TP.0000000000003095","article-title":"Recommended treatment for antibody-mediated rejection after kidney transplantation: the 2019 expert consensus from the Transplantation Society Working Group","volume":"104","author":"Schinstock","year":"2020","journal-title":"Transplantation"},{"key":"2025051205270935600_bib10","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1097\/TP.0000000000004285","article-title":"Anti-interleukin-6 antibody clazakizumab in antibody-mediated renal allograft rejection: accumulation of antibody-neutralized interleukin-6 without signs of proinflammatory rebound phenomena","volume":"107","author":"Borski","year":"2023","journal-title":"Transplantation"},{"key":"2025051205270935600_bib11","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1182\/blood.V85.2.487.487","article-title":"Differentiation of early plasma cells on bone marrow stromal cells requires interleukin-6 for escaping from apoptosis","volume":"85","author":"Kawano","year":"1995","journal-title":"Blood"},{"key":"2025051205270935600_bib12","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1084\/jem.167.2.332","article-title":"The essential role of B cell stimulatory factor 2 (BSF-2\/IL-6) for the terminal differentiation of B cells","volume":"167","author":"Muraguchi","year":"1988","journal-title":"J Exp Med"},{"key":"2025051205270935600_bib13","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1097\/TP.0000000000001452","article-title":"Interleukin-6, A cytokine critical to mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of IL-6 receptor blockade","volume":"101","author":"Jordan","year":"2017","journal-title":"Transplantation"},{"key":"2025051205270935600_bib14","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1681\/ASN.2007070744","article-title":"IL-6\/IL-6R axis plays a critical role in acute kidney injury","volume":"19","author":"Nechemia-Arbely","year":"2008","journal-title":"J Am Soc Nephrol"},{"key":"2025051205270935600_bib15","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.trim.2013.03.003","article-title":"Monoclonal anti-interleukin-6 receptor antibody attenuates donor-specific antibody responses in a mouse model of allosensitization","volume":"28","author":"Wu","year":"2013","journal-title":"Transpl Immunol"},{"key":"2025051205270935600_bib16","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.1097\/TP.0000000000000437","article-title":"Anti-interleukin 6 receptor antibodies attenuate antibody recall responses in a mouse model of allosensitization","volume":"98","author":"Kim","year":"2014","journal-title":"Transplantation"},{"key":"2025051205270935600_bib17","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1111\/ajt.14228","article-title":"Assessment of tocilizumab (anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft recipients","volume":"17","author":"Choi","year":"2017","journal-title":"Am J Transplant"},{"key":"2025051205270935600_bib18","doi-asserted-by":"publisher","first-page":"e13908","DOI":"10.1111\/ctr.13908","article-title":"Early effects of first-line treatment with anti-interleukin-6 receptor antibody tocilizumab for chronic active antibody-mediated rejection in kidney transplantation","volume":"34","author":"Lavacca","year":"2020","journal-title":"Clin Transplant"},{"key":"2025051205270935600_bib19","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1097\/TP.0000000000002895","article-title":"Impact of tocilizumab (anti-IL-6R) treatment on immunoglobulins and anti-HLA antibodies in kidney transplant patients with chronic antibody-mediated rejection","volume":"104","author":"Shin","year":"2020","journal-title":"Transplantation"},{"key":"2025051205270935600_bib20","doi-asserted-by":"publisher","first-page":"91","DOI":"10.6002\/ect.2020.0389","article-title":"Interleukin 6 receptor blockade to treat chronic active antibody-mediated rejection in kidney transplant: a case report with review of relevant literature","volume":"20","author":"Sharma","year":"2022","journal-title":"Exp Clin Transplant"},{"key":"2025051205270935600_bib21","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1080\/21645515.2017.1316909","article-title":"Tocilizumab (Actemra)","volume":"13","author":"Sheppard","year":"2017","journal-title":"Hum Vaccin Immunother"},{"key":"2025051205270935600_bib22","doi-asserted-by":"publisher","first-page":"1364","DOI":"10.3346\/jkms.2010.25.9.1364","article-title":"A case of multicentric Castleman's disease having lung lesion successfully treated with humanized anti-interleukin-6 receptor antibody, tocilizumab","volume":"25","author":"Higuchi","year":"2010","journal-title":"J Korean Med Sci"},{"key":"2025051205270935600_bib23","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1080\/21645515.2017.1316909","article-title":"Tocilizumab (Actemra)","volume":"13","author":"Sheppard","year":"2017","journal-title":"Hum Vaccin Immunother"},{"key":"2025051205270935600_bib24","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1111\/ajt.16391","article-title":"Do anti-IL-6R blockers have a beneficial effect in the treatment of antibody-mediated rejection resistant to standard therapy after kidney transplantation?","volume":"21","author":"Massat","year":"2021","journal-title":"Am J Transplant"},{"key":"2025051205270935600_bib25","doi-asserted-by":"publisher","first-page":"e543","DOI":"10.1097\/TXD.0000000000000988","article-title":"Efficacy and safety of tocilizumab in the treatment of acute active antibody-mediated rejection in kidney transplant recipients","volume":"6","author":"Pottebaum","year":"2020","journal-title":"Transplant Direct"},{"key":"2025051205270935600_bib26","doi-asserted-by":"publisher","first-page":"663","DOI":"10.34067\/KID.0000182019","article-title":"Lack of histological and molecular signature response to tocilizumab in kidney transplants with chronic active antibody mediated rejection: a case series","volume-title":"Kidney360","author":"Kumar","year":"2020"},{"key":"2025051205270935600_bib27","doi-asserted-by":"publisher","first-page":"790547","DOI":"10.3389\/fmed.2021.790547","article-title":"Tocilizumab in the treatment of chronic antibody-mediated rejection post kidney transplantation: clinical and histological monitoring","volume":"8","author":"Noble","year":"2021","journal-title":"Front Med)"},{"key":"2025051205270935600_bib28","doi-asserted-by":"publisher","first-page":"e1638","DOI":"10.1097\/TXD.0000000000001638","article-title":"Absence of IL-6 receptor blockade effect on the outcomes of transplant glomerulopathy in the Absence of anti-HLA donor-specific antibodies","volume":"10","author":"Mella","year":"2024","journal-title":"Transplant Direct"},{"key":"2025051205270935600_bib29","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1002\/art.39249","article-title":"The efficacy and safety of subcutaneous clazakizumab in patients with moderate-to-severe rheumatoid arthritis and an inadequate response to methotrexate: results from a multinational, phase IIb, randomized, double-blind, placebo\/active-controlled, dose-ranging study","volume":"67","author":"Weinblatt","year":"2015","journal-title":"Arthritis Rheumatol"},{"key":"2025051205270935600_bib30","doi-asserted-by":"publisher","first-page":"2163","DOI":"10.1002\/art.39700","article-title":"The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis","volume":"68","author":"Mease","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"2025051205270935600_bib31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1097\/01.tp.0000698592.29821.e5","article-title":"Clazakizumab (anti-IL-6 monoclonal) treatment of patients with chronic & active antibody-mediated rejection post-kidney transplantation (NCT03380377)","volume":"104","author":"Jordan","year":"2020","journal-title":"Transplantation"},{"key":"2025051205270935600_bib32","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.ekir.2022.01.1074","article-title":"Evaluation of clazakizumab (anti-interleukin-6) in patients with treatment-resistant chronic active antibody-mediated rejection of kidney allografts","volume":"7","author":"Jordan","year":"2022","journal-title":"Kidney Int Rep"},{"key":"2025051205270935600_bib33","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1681\/ASN.2020071106","article-title":"A randomized clinical trial of anti-IL-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection","volume":"32","author":"Doberer","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"2025051205270935600_bib34","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1186\/s13063-022-06897-3","article-title":"Clazakizumab for the treatment of chronic active antibody-mediated rejection (AMR) in kidney transplant recipients: phase 3 IMAGINE study rationale and design","volume":"23","author":"Nickerson","year":"2022","journal-title":"Trials"},{"key":"2025051205270935600_bib35","volume-title":"Clazakizumab (CSL300)","author":"Larvol Delta"},{"key":"2025051205270935600_bib36","volume-title":"Clazakizumab for the Treatment of Chronic Active Antibody Mediated Rejection in Kidney Transplant Recipients (IMAGINE)","author":"National Library of Medicine"}],"container-title":["Clinical Kidney Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ckj\/advance-article-pdf\/doi\/10.1093\/ckj\/sfaf108\/62934271\/sfaf108.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ckj\/article-pdf\/18\/5\/sfaf108\/62934271\/sfaf108.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ckj\/article-pdf\/18\/5\/sfaf108\/62934271\/sfaf108.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T05:27:16Z","timestamp":1747027636000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ckj\/article\/doi\/10.1093\/ckj\/sfaf108\/8113983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,15]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2025,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/ckj\/sfaf108","relation":{},"ISSN":["2048-8505","2048-8513"],"issn-type":[{"value":"2048-8505","type":"print"},{"value":"2048-8513","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,5]]},"published":{"date-parts":[[2025,4,15]]},"article-number":"sfaf108"}}