BackgroundNeuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder caused by NOTCH2NLC GGC repeat expansions. Renal involvement in NIID is not well understood.MethodsWe 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, α1-microglobulin, and α2-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.ResultsReduced EPI-eGFR (<90 mL/min/1.73 m2) 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 α1-microglobulin were significantly elevated in the early renal dysfunction group when eGFR remained normal (all p < 0.001). 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: 1.16–13.51, p = 0.028). GGC repeat number showed no overall correlation with eGFR, nor did skin inclusion burden (all p > 0.05). However, in patients with normal renal function, higher GGC repeat number correlated with lower eGFR (ρ = −0.528, p = 0.035). Renal biopsies from two patients with pre-neurological proteinuria revealed characteristic p62-positive intranuclear inclusions in tubular and glomerular cells.ConclusionKidney 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.