Background <p>The safety of sodium-glucose co-transporter 2 inhibitors (SGLT2i) during fasting in patients with chronic kidney disease (CKD) remains underexplored. This study investigates the risk of acute kidney injury (AKI) in patients with CKD who are fasting and taking SGLT2i, and also examines the long-term estimated glomerular filtration rate (eGFR) outcomes over 6 months after fasting.</p> Methods <p>In this prospective cohort study conducted at the Kidney and Urology Centre, Alexandria, Egypt, 236 Muslim patients with CKD were enrolled during Ramadan. Patients were stratified into two groups: SGLT2i users (<i>n</i> = 56) and non-users (<i>n</i> = 180). Weekly serum creatinine and eGFR were monitored during Ramadan, with monthly follow-up for 6 months post-fasting. AKI was defined as an increase in serum creatinine ≥ 0.3 mg/dL. Logistic regression was used to identify AKI predictors.</p> Results <p>The incidence of AKI was 17.8% among SGLT2i users and 23.3% among non-users (RR 0.76; 95% CI 0.41–1.42; <i>p</i> = 0.38), indicating no significant difference. No significant changes were observed in eGFR between the two groups at the end of Ramadan or during the 6-month follow-up. AKI incidence significantly increased with CKD severity (<i>p</i> = 0.036), with 37.5% of CKD stage 5 patients experiencing&#xa0;at least&#xa0;one episode. Logistic regression identified older age and lower baseline eGFR as significant predictors of developing&#xa0;AKI; SGLT2i use was not independently associated&#xa0;with the risk of developing an AKI episode.</p> Conclusion <p>SGLT2i use in CKD patients during Ramadan fasting does not increase the risk of AKI. These findings may&#xa0;offer valuable guidance for clinicians managing fasting patients with CKD on SGLT2i therapy.</p> Graphical abstract <p></p>