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

Официальное название

Efficacy and Safety of Sodium-Glucose Cotransporter-2 Inhibitors in Adolescents With Persistent Albuminuria: A Randomized Controlled Clinical Trial

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Dapagliflozin (10mg Tab)
  Dapagliflozin 10 mg daily
• Препарат Placebo
  Placebo 10 mg daily

Первичные конечные точки

• Albuminuria [Срок оценки: 2, 4 and 6 months]

Вторичные конечные точки (1)

• Glomerular filtration rate [Срок оценки: 2,4 and 6 months]

Критерии участия

Inclusion Criteria:Age 14-18 years

Residence in Aguascalientes

Persistent albuminuria (ACR >30 and <300 mg/g)

Estimated glomerular filtration rate ≥60 mL/min/1.73 m²

No identifiable secondary cause (e.g., lupus, diabetes mellitus)

Renal biopsy showing adaptive podocytopathy or perihilar focal segmental glomerulosclerosis -

Критерии исключения

Hypoalbuminemia

Nephrotic syndrome

Persistent macroalbuminuria (ACR >300 mg/g)

Secondary causes of CKD, including congenital anomalies of the kidney and urinary tract or polycystic kidney disease -

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

Мексика · 1 центр

• Instituto de atención Integral de Enfermedades Renales del Estado de Aguascalientes — Aguascalientes

Публикации

• Agarwal R, Green JB, Heerspink HJL, Mann JFE, McGill JB, Mottl AK, Rosenstock J, Rossing P, Vaduganathan M, Brinker M, Edfors R, Li N, Scheerer MF, Scott C, Nangaku M; CONFIDENCE Investigators. Finerenone with Empagliflozin in Chronic Kidney Disease and Type 2 Diabetes. N Engl J Med. 2025 Aug 7;393(6):533-543. doi: 10.1056/NEJMoa2410659. Epub 2025 Jun 5. PMID 40470996
• Kanbay M, Copur S, Bakir CN, Covic A, Ortiz A, Tuttle KR. Glomerular hyperfiltration as a therapeutic target for CKD. Nephrol Dial Transplant. 2024 Jul 31;39(8):1228-1238. doi: 10.1093/ndt/gfae027. PMID 38308513
• Staplin N, Roddick AJ, Neuen BL, Anker SD, Bhatt DL, Butler J, Cherney DZ, Docherty KF, Fletcher RA, Inzucchi SE, Jardine M, Mahaffey KW, McGuire DK, McMurray JJV, Neal B, Packer M, Patel SM, Perkovic V, Sabatine MS, Solomon S, Vaduganathan M, Wanner C, Wheeler DC, Zannad F, Haynes R, Heerspink HJL, Herrington WG; SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium (SMART-C). Effects PMID 41202026
• Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjostrom CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID 32970396
• The EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, Wanner C, Green JB, Hauske SJ, Emberson JR, Preiss D, Judge P, Mayne KJ, Ng SYA, Sammons E, Zhu D, Hill M, Stevens W, Wallendszus K, Brenner S, Cheung AK, Liu ZH, Li J, Hooi LS, Liu W, Kadowaki T, Nangaku M, Levin A, Cherney D, Maggioni AP, Pontremoli R, Deo R, Goto S, Rossello X, Tuttle KR, Steubl D, Petrini M, Massey D, Eilbracht J, PMID 36331190
• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024 Apr;105(4S):S117-S314. doi: 10.1016/j.kint.2023.10.018. No abstract available. PMID 38490803
• Ortiz A, Arreola Guerra JM, Chan JCN, Jha V, Kramer H, Nicholas SB, Pavkov ME, Wanner C, Wong LP, Cheung M, King JM, Grams ME, Jadoul M, Tuttle KR; Conference Participants. Preventing chronic kidney disease and maintaining kidney health: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2025 Oct;108(4):555-571. doi: 10.1016/j.kint.2025.04.00 PMID 40536455
• Alcalde-Ortiz ML, Jaramillo-Arriaga F, Ibarra-Orenday D, Gonzalez-Dominguez SI, Calzada-Gallegos HD, Pinales-Jimenez AA, Carrillo-Aguilera IA, Flota-Marin DA, Collazo-Zamores MG, Aguirre-Moreno PD, Gutierrez-Hernandez SD, Del Toro-Delgado V, Delgadillo-Castaneda R, Sanchez-Ortiz MDR, Sanchez-Gonzalez I, Ramos-Medellin CL, Chew-Wong A, Macias-Diaz DM, Arreola-Guerra JM. Pediatric kidney dimensions PMID 38280517

Идентификаторы

NCT: NCT07405216 · INAER2026-1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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