The Physiological Basis of Acute GFR Decline With Renoprotective Therapies.

Abstract

Renoprotective therapies including renin-angiotensin system (RAS) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and the nonsteroidal mineralocorticoid receptor antagonist finerenone characteristically produce an acute decline in estimated glomerular filtration rate (eGFR) within the first weeks to months of treatment. As described in the accompanying clinical review, this decline is not only reversible but is linked, paradoxically, to greater long-term renoprotection. The physiological explanation for this apparent contradiction lies in the determinants of glomerular filtration rate and the mechanisms by which the kidney regulates intraglomerular pressure. This review constructs that explanation from the ground up. Beginning with the structural and hemodynamic determinants of GFR, it proceeds through the principal regulatory mechanisms: the myogenic response, tubuloglomerular feedback (TGF), and the neurohormonal signals that continuously adjust arteriolar tone. It then examines how each major renoprotective drug class reduces intraglomerular pressure through distinct arteriolar mechanisms, and distinguishes these hemodynamic mechanisms from the non-hemodynamic basis of the creatinine-based eGFR changes observed with glucagon-like peptide-1 receptor agonists. With this framework, the acute eGFR decline emerges not as a sign of nephrotoxicity but as the expected hemodynamic consequence of successfully reducing glomerular capillary pressure in a kidney that has been chronically operating under injurious levels of intraglomerular hypertension.