{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:31:46Z","timestamp":1786422706775,"version":"build-2736575974"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder caused by\n                      <jats:italic>NOTCH2NLC<\/jats:italic>\n                      GGC repeat expansions. Renal involvement in NIID is not well understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a cross-sectional study of 96 genetically confirmed NIID patients. Renal function was comprehensively assessed using the estimated glomerular filtration rate (eGFR) derived from the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine equation (CKD-EPI 2021; hereafter EPI-eGFR) and a panel of five urinary biomarkers (microalbumin, transferrin, immunoglobulin G, \u03b11-microglobulin, and \u03b12-macroglobulin). Clinical features, GGC repeat number, and skin intranuclear inclusion count were analyzed for their association with renal function. Renal biopsies from two patients with pre-neurological proteinuria were examined for intranuclear inclusions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Reduced EPI-eGFR (&amp;lt;90\u202fmL\/min\/1.73\u202fm\n                      <jats:sup>2<\/jats:sup>\n                      ) was present in 20.8% (20\/96) of patients. Among 44 patients with normal eGFR who underwent urinary testing, 63.6% (28\/44) had abnormal urinary biomarkers. Urinary microalbumin, transferrin, immunoglobulin G and \u03b11-microglobulin were significantly elevated in the early renal dysfunction group when eGFR remained normal (all\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.001). Among individual biomarkers, urinary microalbumin showed the best discrimination for early renal involvement (AUC 0.905). Hypertension was independently associated with reduced eGFR (OR 3.96, 95% CI: 1.16\u201313.51,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.028). GGC repeat number showed no overall correlation with eGFR, nor did skin inclusion burden (all\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;gt;\u202f0.05). However, in patients with normal renal function, higher GGC repeat number correlated with lower eGFR (\n                      <jats:italic>\u03c1<\/jats:italic>\n                      \u202f=\u202f\u22120.528,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.035). Renal biopsies from two patients with pre-neurological proteinuria revealed characteristic p62-positive intranuclear inclusions in tubular and glomerular cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Kidney involvement is common in this hospital-based NIID cohort, with a substantial proportion showing subclinical renal impairment. Sensitive urinary biomarkers may aid early detection before eGFR declines, with microalbumin showing the highest discriminative ability. Hypertension is a potentially modifiable risk factor for reduced eGFR. Genetic burden and skin inclusion burden do not predict renal outcomes, suggesting that secondary mechanisms drive progression. For patients who present with unexplained renal impairment, pathological examination of renal biopsy specimens for intranuclear inclusions may provide critical diagnostic clues.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1905689","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:21:13Z","timestamp":1786422073000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["High burden of kidney involvement in neuronal intranuclear inclusion disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhenxian","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfei","family":"Tai","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaiqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Beijing Tiantan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"China National Clinical Research Center for Neurological Diseases","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1372","DOI":"10.1212\/WNL.0b013e3182166e13","article-title":"Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease","volume":"76","author":"Sone","year":"2011","journal-title":"Neurology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1038\/s41588-019-0459-y","article-title":"Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease","volume":"51","author":"Sone","year":"2019","journal-title":"Nat Genet"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1136\/jmedgenet-2019-106268","article-title":"Long-read sequencing identified repeat expansions in the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease","volume":"56","author":"Deng","year":"2019","journal-title":"J Med Genet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1016\/j.ajhg.2019.05.013","article-title":"Expansion of human-specific GGC repeat in neuronal Intranuclear inclusion disease-related disorders","volume":"105","author":"Tian","year":"2019","journal-title":"Am J Hum Genet"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"3170","DOI":"10.1093\/brain\/aww249","article-title":"Clinicopathological features of adult-onset neuronal intranuclear inclusion disease","volume":"139","author":"Sone","year":"2016","journal-title":"Brain"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1111\/neup.12792","article-title":"The clinical and neuropathological picture of adult neuronal intranuclear inclusion disease with no radiological abnormality","volume":"42","author":"Miki","year":"2022","journal-title":"Neuropathology"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1212\/WNL.0000000000006480","article-title":"Neuronal intranuclear inclusion disease showing intranuclear inclusions in renal biopsy 12 years 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mechanisms in kidney fibrosis","volume":"124","author":"Duffield","year":"2014","journal-title":"J Clin Invest"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1017\/cjn.2021.514","article-title":"The clinical and neuroimaging features of sporadic adult-onset neuronal intranuclear inclusion disease","volume":"50","author":"Ni","year":"2023","journal-title":"Can J Neurol Sci"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"e7730","DOI":"10.1002\/ccr3.7730","article-title":"A case of unusual renal manifestation in a patient with neuronal intranuclear inclusion disease treated with steroids","volume":"11","author":"Morita","year":"2023","journal-title":"Clin Case Reports"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1905689\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:21:14Z","timestamp":1786422074000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1905689\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":32,"alternative-id":["10.3389\/fneur.2026.1905689"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1905689","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"article-number":"1905689"}}