Erik Moedt, Akihiko Koshino, Niels Jongs, Wenjun Ju, Viji Nair, Matthias Kretzler, Michael K. Hansen, Clare G. Arnott, David Wheeler, Peter Rossing, Steven G. Coca, Ann Hammarstedt, Peter J. Greasley, Petter Bjornstad, Stephan J.L. Bakker, Hiddo J.L. Heerspink
KEY POINTS: Lower urinary EGF levels, normalized to urinary creatinine, reflected impaired tubular health and were associated with higher kidney risk across CKD. Sodium-glucose cotransporter 2 inhibitors attenuated the decline in urinary EGF-creatinine ratio observed with placebo, supporting a role in maintaining tubular health. Early increases in urinary EGF-creatinine ratio were linked to lower kidney risk, adding prognostic value beyond albuminuria. BACKGROUND: Urinary EGF is a marker of tubular repair capacity. Lower urinary EGF-creatinine ratio (uEGF/Cr) levels associate with kidney disease progression in patients with type 2 diabetes at early stages of CKD. In these patients, sodium-glucose cotransporter 2 inhibitors (SGLT2is) are associated with increased tubular EGF expression. In this study, we aimed to extend these findings to a broad CKD population with and without type 2 diabetes at various stages of CKD. METHODS: We measured EGF in stored urine samples at baseline and year 1 in participants from the Canagliflozin Cardiovascular Assessment Study (CANVAS), Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE), and Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) clinical trials. Associations of baseline and longitudinal uEGF/Cr with the composite kidney outcome (sustained ≥40% eGFR decline, kidney failure, or kidney-related death) were assessed using multivariable Cox regression, and associations with annual eGFR decline using a two-slope linear mixed-effects model. Treatment effects of SGLT2i on uEGF/Cr over time were analyzed with analysis of covariance. RESULTS: In participants with type 2 diabetes from the CANVAS and CREDENCE trials ( N =5978), higher baseline uEGF/Cr was associated with a lower risk of the composite kidney outcome (hazard ratio per two-fold higher uEGF/Cr, 0.87 [95% confidence interval, 0.80 to 0.94]). SGLT2i attenuated the decline in uEGF/Cr over 1 year compared with placebo by 6.7% (95% confidence interval, 2.5 to 10.8). Increases in uEGF/Cr from baseline to year 1 were independently associated with a lower risk of the kidney outcome, even after accounting for 1-year changes in albuminuria, eGFR, and other clinical variables. Replication analyses showed similar results in the DAPA-CKD trial ( N =2450), with consistent findings in participants with and without diabetes. CONCLUSIONS: These results extend previous findings, supporting uEGF/Cr as a robust, independent biomarker of tubular health and kidney risk across diverse CKD populations. SGLT2i attenuated uEGF/Cr decline, and early changes in uEGF/Cr provided prognostic information beyond albuminuria.