{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T17:44:15Z","timestamp":1782755055923,"version":"3.54.5"},"reference-count":33,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by variable clinical behavior and diverse molecular phenotypes. Although immune checkpoint inhibitors and targeted therapies have transformed the treatment landscape of advanced RCC, clinically validated biomarkers capable of improving risk stratification, therapeutic-decision making and disease monitoring remain lacking. Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 (HAVCR1) or T-cell immunoglobulin and mucin domain-containing protein-1 (TIM-1), has emerged as a biologically compelling investigational biomarker e because of its close relationship to proximal tubular epithelial injury and renal carcinogenesis. KIM-1 is a transmembrane glycoprotein minimally expressed in normal kidney tissue but markedly upregulated in dedifferentiated proximal tubular epithelial cells following injury, and in clear cell RCC, where its extracellular domain can be shed into plasma and urine. Beyond its role as a marker of tubular injury, KIM-1 participates in immune regulation, phagocytosis, inflammatory signaling and tissue remodeling, supporting its potential relevance to tumor biology. Clinical studies have demonstrated associations between elevated circulating KIM-1 levels and RCC diagnosis, recurrence risk, and survival outcomes, particularly in localized and postoperative disease settings. KIM-1 has additionally been investigated as a therapeutic target through antibody\u2013drug conjugate approaches. Despite promising translational data, important limitations yet remain. Current evidence is predominantly prognostic rather than predictive, and substantial analytical and biological challenges continue to limit implementation. Assay standardization, clinically meaningful cutoffs, specimen selection, timing of sampling, and confounding by chronic kidney disease or nonmalignant renal injury remain incompletely resolved. Furthermore, evidence supporting incremental value beyond established clinicopathologic models remains limited. This review critically evaluates the biological rationale, analytical considerations and clinical evidence supporting KIM-1 in RCC. Particular emphasis is placed on distinguishing prognostic, predictive, pharmacodynamic, and therapeutic applications, as well as defining the evidentiary gaps that must be addressed before clinical implementation. Current evidence is derived predominantly from retrospective and exploratory analyses, and important limitations remain regarding assay standardization, biological specificity, chronic kidney disease-related confounding, and prospective validation. The review concludes with a summary of the evolving landscape of KIM-1-directed biomarker strategies in RCC, which may ultimately contribute to improved biologic risk stratification and biomarker-driven clinical investigation in RCC.<\/jats:p>","DOI":"10.3390\/curroncol33070378","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T18:35:05Z","timestamp":1782239705000},"page":"378","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kidney Injury Molecule-1 (KIM-1) in Renal Cell Carcinoma: Biological Foundations and Emerging Clinical Applications"],"prefix":"10.3390","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6962-724X","authenticated-orcid":false,"given":"Jason King","family":"Talao","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada"},{"name":"Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohann","family":"Correa","sequence":"additional","affiliation":[{"name":"Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"},{"name":"Division of Radiation Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8845-1126","authenticated-orcid":false,"given":"Lakshman","family":"Gunaratnam","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada"},{"name":"Matthew Mailing Centre for Translational Transplant Studies, London Health Sciences Centre Research Institute, London, ON N6A 5A5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7195-8246","authenticated-orcid":false,"given":"Ricardo","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada"},{"name":"Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada"},{"name":"Cancer Research Laboratory Program, Lawson Health Research Institute, London, ON N6A 4L6, Canada"},{"name":"Department of Oncology, London Health Sciences Centre, Western University, 800 Commissioners Road East, Room A3-940, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","first-page":"216","article-title":"Renal cell carcinoma","volume":"361","author":"Rini","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s40425-016-0180-7","article-title":"Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of renal cell carcinoma","volume":"4","author":"Rini","year":"2016","journal-title":"J. Immunother. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1056\/NEJMoa2035716","article-title":"Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma","volume":"384","author":"Motzer","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1074\/jbc.273.7.4135","article-title":"Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury","volume":"273","author":"Ichimura","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1046\/j.1523-1755.2002.00433.x","article-title":"Kidney injury molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury","volume":"62","author":"Han","year":"2002","journal-title":"Kidney Int."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1681\/ASN.2004070530","article-title":"Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma","volume":"16","author":"Han","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s11255-013-0522-z","article-title":"Urine kidney injury molecule-1: A potential non-invasive biomarker for patients with renal cell carcinoma","volume":"46","author":"Zhang","year":"2014","journal-title":"Int. Urol. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1158\/0008-5472.CAN-13-1671","article-title":"HAVCR\/KIM-1 activates the IL-6\/STAT-3 pathway in clear cell renal cell carcinoma and determines tumor progression and patient outcome","volume":"74","author":"Cuadros","year":"2014","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1200\/JCO.23.00699","article-title":"Plasma kidney injury molecule-1 for preoperative prediction of renal cell carcinoma versus benign renal masses, and association with clinical outcomes","volume":"42","author":"Xu","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1016\/j.annonc.2025.08.007","article-title":"Circulating kidney injury molecule-1 (KIM-1) and association with outcome to adjuvant immunotherapy in renal cell carcinoma","volume":"36","author":"Rini","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"F552","DOI":"10.1152\/ajprenal.00285.2002","article-title":"Kidney injury molecule-1: A tissue and urinary biomarker for nephrotoxicant-induced renal injury","volume":"286","author":"Ichimura","year":"2004","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/nri1111","article-title":"The TIM gene family: Emerging roles in immunity and disease","volume":"3","author":"Kuchroo","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1172\/JCI34487","article-title":"Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells","volume":"118","author":"Ichimura","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1172\/JCI75417","article-title":"KIM-1-mediated phagocytosis reduces acute injury to the kidney","volume":"125","author":"Yang","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2704","DOI":"10.1681\/ASN.2007030325","article-title":"Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinase and juxtamembrane region","volume":"18","author":"Zhang","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1172\/JCI45361","article-title":"Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis","volume":"123","author":"Humphreys","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1007\/s11255-025-04447-9","article-title":"Liquid-based kidney injury molecule-1 as a diagnostic and prognostic indicator in renal cell carcinoma: A systematic review and meta-analysis","volume":"57","author":"He","year":"2025","journal-title":"Int. Urol. Nephrol."},{"key":"ref_18","unstructured":"FDA-NIH Biomarker Working Group (2016). BEST (Biomarkers, EndpointS, and Other Tools) Resource."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/469156a","article-title":"Bring on the biomarkers","volume":"469","author":"Poste","year":"2011","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1093\/jnci\/djp335","article-title":"Use of archived specimens in evaluation of prognostic and predictive biomarkers","volume":"101","author":"Simon","year":"2009","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1681\/ASN.2013070758","article-title":"Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes","volume":"25","author":"Sabbisetti","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.euf.2025.04.006","article-title":"Future Directions for Circulating Tumor DNA Studies in Renal Cell Carcinoma","volume":"11","author":"Ayanambakkam","year":"2025","journal-title":"Eur. Urol. Focus"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1038\/s41698-025-00876-y","article-title":"Circulating tumor DNA to monitor treatment response in solid tumors and advance precision oncology","volume":"9","author":"Bartolomucci","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s13244-025-02164-6","article-title":"From Radiomics to Radiogenomics: Decoding Renal Cell Carcinoma Biology for Precision Medicine\u2014A Narrative Review","volume":"16","author":"He","year":"2025","journal-title":"Insights Imaging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-med-070623-045906","article-title":"CD70: An Emerging Anticancer Target in Renal Cell Carcinoma and Beyond","volume":"76","author":"Zang","year":"2025","journal-title":"Annu. Rev. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/s41591-018-0053-3","article-title":"Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma","volume":"24","author":"McDermott","year":"2018","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1038\/s41591-020-1044-8","article-title":"Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: Biomarker analysis of the phase 3 JAVELIN Renal 101 trial","volume":"26","author":"Motzer","year":"2020","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s12967-024-04848-x","article-title":"Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics","volume":"22","author":"Yang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"M\u00fchlbauer, J., Egen, L., Kowalewski, K.-F., Grilli, M., Walach, M.T., Westhoff, N., Nuhn, P., Laqua, F.C., Baessler, B., and Kriegmair, M.C. (2021). Radiomics in Renal Cell Carcinoma\u2014A Systematic Review and Meta-Analysis. Cancers, 13.","DOI":"10.3390\/cancers13061348"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e31816","DOI":"10.1016\/j.heliyon.2024.e31816","article-title":"Identification of clear cell renal cell carcinoma subtypes by integrating radiomics and transcriptomics","volume":"10","author":"Gao","year":"2024","journal-title":"Heliyon"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1093\/jnci\/93.14.1054","article-title":"Phases of biomarker development for early detection of cancer","volume":"93","author":"Pepe","year":"2001","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1056\/NEJMoa2106391","article-title":"Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma","volume":"385","author":"Choueiri","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1007\/s10637-020-00945-y","article-title":"Safety and efficacy of CDX-014, an antibody-drug conjugate directed against T cell immunoglobulin mucin-1 in advanced renal cell carcinoma","volume":"38","author":"McGregor","year":"2020","journal-title":"Investig. New Drugs"}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/7\/378\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:50:18Z","timestamp":1782751818000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/33\/7\/378"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["curroncol33070378"],"URL":"https:\/\/doi.org\/10.3390\/curroncol33070378","relation":{},"ISSN":["1718-7729"],"issn-type":[{"value":"1718-7729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]}}}