{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:33:43Z","timestamp":1791999223055,"version":"4.4.0"},"reference-count":49,"publisher":"BMJ","issue":"1","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"unspecified","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Massachusetts General Hospital Claflin Distinguished Scholar Award"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,1,2]]},"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of\n                      <jats:italic>IL2RA,<\/jats:italic>\n                      IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9\u20133.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5\u20130.9, p&lt;0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7\u20131.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve &gt;96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for\n                      <jats:italic>IL2RA<\/jats:italic>\n                      , IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-006222","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T10:45:22Z","timestamp":1674125122000},"page":"e006222","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis"],"prefix":"10.1136","volume":"11","author":[{"given":"Meghan E","family":"Sise","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4959-7437","authenticated-orcid":false,"given":"Qiyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harish","family":"Seethapathy","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiana","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Destiny","family":"Harden","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Neal","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy A","family":"Rosales","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert B","family":"Colvin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Chute","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn D","family":"Cornell","sequence":"additional","affiliation":[{"name":"Department of Pathology, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3700-4537","authenticated-orcid":false,"given":"Sandra M","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Nephrology & Hypertension, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riley","family":"Fadden","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5344-6645","authenticated-orcid":false,"given":"Ryan J","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Barmettler","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Wells","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5747-2151","authenticated-orcid":false,"given":"Shruti","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA"},{"name":"Department of Oncology, Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra-Chloe","family":"Villani","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, 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