Trends in nephrology: kidney metabolism as a therapeutic target

Chronic kidney disease (CKD) represents a major global health burden, characterized by high prevalence, rising mortality and disability, and substantial economic and environmental impact.New therapies to tackle this disease spectrum are therefore urgently needed.For decades, nephrology has focused on structural and hemodynamic paradigms of CKD, emphasizing albuminuria, blood pressure control and glycemic control as key treatment targets.This concept suggested that slowing CKD progression required glomerular pressure reduction through angiotensin II inhibition, with limited targeting of the underlying metabolic dysfunction.However, despite optimized renin-angiotensin-aldosterone system blockade, patients with CKD continued to face high residual risks for kidney failure and cardiovascular death.Even as sodium-glucose cotransporter 2 (SGLT2) inhibitors demonstrated clear benefits in outcome trials, their efficacy was initially attributed to glycemic control or hemodynamic effects in diabetes.Yet, these explanations proved insufficient: this drug class reduced CKD progression in patients without diabetes, improved heart failure outcomes independent of albuminuria, and were effective across a wide range of estimated glomerular filtration rate (eGFR) and proteinuria levels [1 ].Moreover, no single pathway could fully account for their broad effects [2 ].Despite growing evidence and the long-known role of the kidney as the main excretory metabolic organ, its complex metabolic functions as central contributors to disease progression has been overlooked.In the last decade, metabolism has emerged as an underlying principle of kidney disease.Kidneys under chronic stress exhibit metabolic changes, marking a shift in our understanding of CKD pathogenesis.While glomerular injury and hemodynamic overload have long been considered key drivers, recent genetic, translational and experimental data have repositioned the proximal tubule as the metabolic core of the diseased kidney [3 ].Mechanistically, chronic insults-such as hypertension, hyperglycemia or aging-activate a hierarchy of nutrient-and injury-sensing pathways that culminate in mitochondrial dysfunction [4 , 5 ].The failure of the mitochondria, the powerhouses of the cell, is central to disease progression with fibrosis and nephron loss.But how do we get there?Proximal tubular cells, with their high energy demand, rely on several substrates to maintain their energy metabolism.Glucose, amino acids and fatty acids are therefore constantly transported with high fluxes into the cells.If the kidney is overloaded with metabolites in constant exposure (increased workload) [6 ] bioenergetic mismatch develops through