SGLT2i, anti-endothelin A and double endothelin and angiotensin inhibitors: a new future for chronic kidney disease in children

Chronic kidney disease (CKD) in childhood, although uncommon, has profound lifelong consequences. Because disease onset occurs early, even modest slowing of CKD progression may translate into decades free from dialysis, transplantation, and premature death. Progressive proteinuria is a central driver of nephron loss in pediatric CKD, making early and sustained antiproteinuric strategies particularly impactful. Despite heterogeneous etiologies, including congenital and immune-mediated kidney diseases, CKD progression in children converges on shared mechanisms such as glomerular hypertension, podocyte injury, tubular epithelial dysfunction, and fibrosis. Targeting these final common pathways offers the greatest opportunity to modify long-term outcomes. Several emerging pharmacological strategies are reshaping the therapeutic landscape of CKD. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) reduce intraglomerular pressure by restoring tubuloglomerular feedback and exert additional natriuretic, metabolic, and anti-inflammatory effects. Endothelin A (ETA) receptor antagonists counteract endothelin-1–mediated vasoconstriction, inflammation, and fibrotic remodeling, key drivers of proteinuric kidney damage. Dual endothelin–angiotensin receptor antagonists (DEARAs) integrate selective ETA blockade with angiotensin II type 1 receptor inhibition, simultaneously suppressing two tightly interconnected pathways that amplify glomerular hypertension, podocyte injury, and fibrosis. Robust randomized trials support the efficacy and safety of these agents in adults, whereas pediatric evidence remains limited, particularly regarding long-term safety. In this review, we summarize the mechanistic rationale and available clinical data for these novel antiproteinuric therapies in children, highlighting ongoing trials and key knowledge gaps relevant to future pediatric CKD management.