Proximal Tubular Secretory Clearance: A Neglected Partner of Kidney Function

Abstract

The secretion of small molecules by the proximal tubules of the kidneys represents a vital homeostatic function for rapidly clearing endogenous solutes and medications from the circulation. After filtration at the glomerulus, renal blood flow is directed through a network of peritubular capillaries, where transporters of the proximal tubules actively secrete putative uremic toxins and hundreds of commonly prescribed drugs into the urine, including protein-bound substances that cannot readily cross the glomerular basement membrane. Despite its central physiologic importance, tubular secretory clearance is rarely measured or even estimated in clinical or research settings. Major barriers to estimating tubular solute clearance include uncertainty regarding optimal endogenous secretory markers and a lack of standardized laboratory assays. The creation of new methods to measure tubular secretion could catalyze advances in kidney disease research and clinical care. Differences in secretory clearance relative to the GFR could help distinguish among the causes of CKD, particularly for disorders that primarily affect the tubulointerstitium. As the primary mechanism by which the kidneys excrete medications, tubular secretory clearance offers promise for improving kidney medication dosing, which is currently exclusively on the basis of filtration. The differing metabolic profiles of retained solutes eliminated by secretion versus glomerular filtration suggest that secretory clearance could uniquely inform uremic toxicity, refine existing measures of residual kidney function, and improve prediction of cardiovascular and kidney disease outcomes. Interdisciplinary research across clinical, translational, and laboratory medicine is needed to bring this often neglected kidney function into the limelight.

Keywords: Capillaries; Chronic; Glomerular Basement Membrane; Interdisciplinary Research; Metabolome; Renal Circulation; Renal Insufficiency; Uncertainty; chronic kidney disease; creatinine clearance; drug excretion; glomerular filtration rate; kidney; proximal tubule; renal proximal tubule cell; tubule cells; uremia.

Figure 1.

The proximal tubule transports numerous solutes and medications. Secreted solutes enter the interstitium and are transported into proximal tubular cells via basolateral transporters, including organic anion transporter 1 (OAT1), OAT2, OAT3, and organic cation transporter 2 (OCT2). Solutes are then secreted into the urine via energy-dependent apical transporters. OA, organic anion; OC, organic cation; K, potassium; αKG, α-ketoglutarate; Na, sodium; NaDC3, renal sodium-dependent dicarboxylate transporter.