Development and Clinical Application of a Multiplexed Assay for Proximal Tubular Secretion

Abstract

Proximal tubular secretion contributes to the elimination of metabolites, uremic toxins, and many medications, yet existing clinical tools rely on glomerular filtration markers with no common way to evaluate secretory capacity. A multiplexed targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for 21 tubular secretory solutes (TSS) in plasma and urine, for measurement of solute clearance as an estimate of tubular secretory capacity. In a cohort of healthy adults and patients with chronic kidney disease (CKD) (n = 48), several solutes, including N2,N2-dimethylguanosine (DMG), correlated strongly with the clearance of furosemide and famciclovir, supporting their potential as secretory biomarkers. In a critically ill cohort (n = 246), baseline TSS clearances were associated with incident acute kidney injury (AKI) and major adverse kidney events at 30 days (MAKE30), and baseline inverse plasma DMG declined progressively across AKI stages. These findings support tubular secretory function as a clinically meaningful dimension of kidney physiology and identify DMG as a promising early biomarker of secretory impairment in critically ill patients.