Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Adolescents With Early Stages of Chronic Kidney Disease

Overview

Chronic kidney disease (CKD) is highly prevalent in the state of Aguascalientes, Mexico, particularly among adolescents and young adults. Epidemiologic and histologic studies suggest that this burden is largely driven by reduced nephron endowment of prenatal origin, leading to compensatory glomerular hyperfiltration, adaptive podocytopathy, and persistent albuminuria at early stages of disease. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated nephroprotective effects in adult populations with CKD, including reductions in albuminuria and slowing of disease progression, independent of diabetes status. However, no randomized controlled trials have evaluated the efficacy and safety of SGLT2 inhibitors in adolescents with early-stage CKD and persistent albuminuria. This randomized, double-blind, placebo-controlled clinical trial aims to evaluate whether treatment with an SGLT2 inhibitor reduces albuminuria in adolescents aged 14 to 18 years with persistent microalbuminuria (albumin-to-creatinine ratio 30-300 mg/g) and preserved kidney function. Participants will be randomized in a 2:1 ratio to receive dapagliflozin 10 mg daily or placebo for six months. The primary outcome is the change in urinary albumin-to-creatinine ratio from baseline to six months. Secondary outcomes include changes in estimated glomerular filtration rate and safety outcomes.

Chronic kidney disease (CKD) is a major global health problem and represents one of the fastest-growing causes of mortality worldwide. In the state of Aguascalientes, Mexico, CKD prevalence is among the highest reported globally, with an unusually high burden affecting adolescents and young adults. Statewide screening programs and renal biopsy registries have identified a distinct epidemiologic and histologic pattern in this region. Adolescents with early-stage CKD frequently present with persistent albuminuria, glomerulomegaly, absence of interstitial fibrosis, and adaptive podocytopathy, findings consistent with reduced nephron endowment of prenatal origin. Over time, these lesions may progress to adaptive focal segmental glomerulosclerosis and clinically significant CKD in young adulthood. The predominant pathogenic mechanism in this population is believed to be glomerular hyperfiltration. Pharmacologic therapies targeting hyperfiltration have proven efficacy in slowing CKD progression. Renin-angiotensin-aldosterone system inhibitors are standard of care, and more recently, sodium-glucose cotransporter-2 inhibitors have demonstrated substantial nephroprotective effects in adult populations, including patients without diabetes and across a wide range of albuminuria levels. Despite this evidence, adolescents and patients with early-stage CKD (G1-G2 A2) have been systematically excluded from major randomized trials. This study is a randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of an SGLT2 inhibitor in adolescents with persistent albuminuria and preserved kidney function. Eligible participants are adolescents aged 14 to 18 years residing in Aguascalientes with persistent microalbuminuria (albumin-to-creatinine ratio 30-300 mg/g), estimated glomerular filtration rate ≥60 mL/min/1.73 m², and no identifiable secondary cause of kidney disease. After screening and baseline evaluation-including medical history, laboratory testing, immunologic studies, and renal ultrasound-eligible participants will be randomized in a 2:1 ratio to receive dapagliflozin 10 mg daily or matching placebo for a total duration of six months. All participants will receive standardized nutritional counseling. Follow-up visits will occur every two months and will include clinical assessment, physical examination, blood pressure measurement, and laboratory testing. Urinary albumin-to-creatinine ratio will be measured using standardized laboratory methods. The primary endpoint is the change in urinary albumin-to-creatinine ratio from baseline to six months, analyzed using log-transformed values. Secondary endpoints include changes in estimated glomerular filtration rate and assessment of safety outcomes, including adverse events such as hypotension and urinary tract infections. This trial seeks to generate high-quality evidence on the efficacy and safety of SGLT2 inhibitors in adolescents with early-stage CKD, a population with a disproportionate disease burden and limited therapeutic evidence.