Association of Urinary Epidermal Growth Factor with Kidney Outcomes and Effects of Sodium-Glucose Cotransporter 2 Inhibition.
prospective_cohort · Level II
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- Also identified by DOI 10.1681/ASN.0000001086.
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Abstract
Urinary epidermal growth factor (uEGF) is a marker of tubular repair capacity. Lower uEGF-to-creatinine ratio (uEGF/Cr) levels associate with kidney disease progression in patients with type 2 diabetes at early stages of chronic kidney disease (CKD). In these patients, sodium-glucose cotransporter 2 inhibitors (SGLT2i) 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. We measured EGF in stored urine samples at baseline and year 1 in participants from the CANVAS, CREDENCE, and 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. 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 2-fold higher uEGF/Cr: 0.87 [95% CI 0.80, 0.94]). SGLT2i attenuated the decline in uEGF/Cr over 1-year compared to placebo by 6.7% (95% CI 2.5, 10.8). Increases in uEGF/Cr from baseline to year 1 were independently associated with a reduced 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. These results extend previous findings, supporting uEGF/Cr as a robust, independent biomarker of tubular health and kidney risk across diverse CKD populations. SGLT2i attenuate uEGF/Cr decline, and early changes in uEGF/Cr provide prognostic information beyond albuminuria.