The relationship between in-stent neoatherosclerosis (ISNA) and chronic kidney disease (CKD) was investigated among patients exhibiting in-stent restenosis (ISR) after drug-eluting stent (DES) implantation. A total of 220 patients with confirmed in-stent restenosis (ISR) via coronary arteriography between 2020 and 2023 were enrolled. Patients were stratified into three groups based on estimated glomerular filtration rate (eGFR) levels: (1) normal renal function (eGFR ≥ 90 mL/min/1.73 m², n = 80), (2) mild renal impairment (60 ≤ eGFR < 90 mL/min/1.73 m², n = 86), and (3) kidney failure (eGFR < 60 mL/min/1.73 m², n = 54). Baseline clinical characteristics, angiographic parameters, and optical coherence tomography (OCT) data were collected and analyzed across all groups. No significant differences in angiographic characteristics were found between the three groups (p > 0.05). Patients with kidney failure demonstrated significantly higher rates of both in-stent neoatherosclerosis (ISNA) (68.5% vs. 46.5% vs. 42.5%; p < 0.05) and thin-cap fibroatheroma (TCFA) within ISR lesions (40.7% vs. 22.1% vs. 22.5%; p < 0.05) compared to those with mild or normal renal function, respectively. Lower eGFR levels were associated with a higher incidence of ISNA and reduced neointima stability.