{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T08:43:09Z","timestamp":1792658589573,"version":"4.5.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,8,15]],"date-time":"2025-08-15T00:00:00Z","timestamp":1755216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["MR1-2022-12375953"],"award-info":[{"award-number":["MR1-2022-12375953"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The discovery of circulating autoantibodies targeting slit diaphragm proteins\u2014particularly nephrin, podocin and Kirrel1\u2014has redefined the pathogenic framework of nephrotic syndrome (NS), shifting the focus from empirical, morphology-based classification to a mechanistic, biomarker-driven model. This evolution holds promise for earlier, non-invasive diagnosis, individualized risk stratification and tailored immunomodulatory therapy. However, the translation of these insights into clinical practice requires reliable serum assays but biological complexity and technical variability remain challenging. In this review we identify five hurdles to unlock the full diagnostic and therapeutic utility of anti-slit diaphragm autoantibodies. First, the low or transient serum levels of anti-nephrin antibodies reflect their rapid onset of NS and autoantibody loss into the urine, making timing of sample collection essential. Second, antibody levels closely mirror immunological activity and proteinuria levels\u2014rising during relapse and falling in remission\u2014rendering detection highly phase-dependent. Third, autoimmune NS are various, which complicates diagnosis. Up to 25% of pediatric and adult NS are negative for anti-nephrin immunoglobulin G (IgG) but positive for anti-podocin IgG, and anti-Kirrel1 autoimmunity, though rare, also occurs. Overlapping profiles and epitope spreading underscore the limitations of single-target assays. Fourth, assay performance is influenced by antigen fragment selection, expression system, and post-translational modifications\u2014especially for nephrin, which is structurally complex and heavily glycosylated. Finally, combined serological and tissue-based strategies\u2014particularly those integrating enzyme-linked immunosorbent assay (ELISA) with super-resolution microscopy are a gold standard needed to determine sensitivity and specificity of serum ELISA and reliably inform therapeutic decision-making. Here we will discuss a roadmap for the clinical implementation of anti-nephrin, anti-podocin and anti-Kirrel1 (anti-slit diaphragm) antibody testing, which lays the foundation for precision diagnostics and personalized treatment in autoimmune podocytopathies.<\/jats:p>","DOI":"10.1093\/ndt\/gfaf156","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T11:59:01Z","timestamp":1755172741000},"page":"428-436","source":"Crossref","is-referenced-by-count":16,"title":["Anti-nephrin, anti-podocin and anti-Kirrel1 antibodies: biological challenges and clinical implications"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6610-3251","authenticated-orcid":false,"given":"Valentina","family":"Raglianti","sequence":"first","affiliation":[{"name":"Experimental and Clinical Sciences \u201cMario Serio\u201d, University of Florence Department of Biomedical, , Florence ,","place":["Italy"]},{"name":"Nephrology and Dialysis Unit, Meyer Children's Hospital IRCCS , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Lucia","family":"Angelotti","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Sciences \u201cMario Serio\u201d, University of Florence Department of Biomedical, , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letizia","family":"De Chiara","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Sciences \u201cMario Serio\u201d, University of Florence Department of Biomedical, , Florence ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1774-8088","authenticated-orcid":false,"given":"Paola","family":"Romagnani","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Sciences \u201cMario Serio\u201d, University of Florence Department of Biomedical, , Florence 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