BACKGROUND: Diabetic kidney disease (DKD) and diabetic retinopathy (DR) represent two major microvascular complications of diabetes mellitus (DM). Previous studies have suggested that renin-angiotensin system inhibitors (RASi) exert protective effects on both DKD and DR. However, their specific impact on retinal microvascular parameters (RMPs), as well as the association between changes in fundus microvasculature and alterations in renal clinical parameters, remains unclear. This pilot study aimed to quantitatively assess the short-term effects of RASi on retinal microvasculature in patients with DKD using an artificial intelligence (AI)-based analysis of ultra-wide-field (UWF) fundus images. METHODS: In this prospective cohort study, 27 patients with DKD were enrolled between July 2023 and September 2024. UWF fundus images were acquired at baseline and 12 weeks after initiation of RASi therapy. A validated deep learning AI model was employed to segment retinal vessels and quantify RMPs, including fractal dimension (Df) and tortuosity (TORT), in both the central and peripheral retinal regions. Statistical analyses for pre- and post-treatment comparisons were performed using a linear mixed-effects model with patient ID as a random intercept. or a Wilcoxon signed-rank test, as appropriate. Changes in these parameters post-treatment were analyzed and correlated with alterations in clinical renal indicators. RESULTS: Among the enrolled patients, 21 patients (77.8%) were male, with a mean age of 55.7 ± 14.2 years, a mean diabetes duration of 9.9 ± 6.6 years, a baseline estimated glomerular filtration rate (eGFR) of 73.7 ± 18.5 mL/min/1.73 m², and a median proteinuria of 0.57 (0.25, 0.97) g/24h. Fifteen patients (55.6%) had diabetic retinopathy (DR). After 12 weeks of RASi treatment, significant decreases were observed within the UWF images in venous Df (adjusted p = 0.0389) for the overall cohort, and venous TORT (adjusted p = 0.0496) for No-DR and NPDR groups. These significant changes were not observed in parameters derived from the central retinal region. CONCLUSION: RASi therapy might be associated with retinal peripheral venous alterations, providing clues to a vascular- and topography-specific therapeutic response and shedding light on a potential imaging biomarker for diabetes management.