Functional, Hemodynamic and Molecular Determinants for Evaluating the Efficacy of Sodium-glucose Cotransporter-2 Inhibitor Therapy in Diabetic Kidney Disease.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have changed the treatment of diabetic kidney disease (DKD) by lowering the risk of kidney failure and cardiovascular events in several large trials. The tools that clinicians rely on include estimated glomerular filtration rate (eGFR) and the urinary albumin-to-creatinine ratio, which capture only part of the pharmacological action of these molecules. This review examines the biochemical, hemodynamic, and molecular determinants of SGLT2 inhibitor treatment efficacy in DKD, together with the physiology that links each marker to treatment response. The markers are grouped into functional and hemodynamic measures (the early eGFR dip, chronic eGFR slope, and cystatin C); albuminuria, which remains the central glomerular readout; tubular markers (uromodulin, α1-microglobulin, Dickkopf-3, NGAL, kidney injury molecule-1, and L-FABP); markers of inflammation and fibrosis (tumour necrosis factor receptors 1 and 2, interleukin-6, matrix metalloproteinase-7, and fibronectin-1); and cardiorenal and systemic markers (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin, growth differentiation factor-15, hematocrit, and uric acid). Recent evidence from EMPA-KIDNEY, CREDENCE, and CANVAS studies, as well as the urinary peptidomic classifier CKD273, are discussed. We propose a practical biomarker-guided algorithm for DKD management based on current evidence. Most markers remain investigational and will require assay standardization and prospective validation before routine use.