Metabolomic Profiling Identifies New Endogenous Markers of Tubular Secretory Clearance. Issue 1 (20th January 2023)

• Record Type: Journal Article
• Authors: Granda, Michael L.; Prince, David K.; Fiehn, Oliver; Chen, Yan; Rajabi, Tanya; Yeung, Catherine K.; Hoofnagle, Andrew N.; Kestenbaum, Bryan
• Is Part Of: Kidney360. Volume 4:Issue 1(2023)
• Page Start: 23
• Page End: 31
• Publication Date: 2023-01-20
• Subjects: chronic kidney disease -- diuretics -- kidney function -- metabolomics -- proximal tubule -- renal proximal tubule cell -- secretion -- secretory clearance -- tubular secretion -- uremia; 616.61
• DOI: 10.34067/KID.0004172022
• Languages: English
• ISSNs: 2641-7650

Abstract

Abstract : Abstract : Key Points: Proximal tubular secretion is a primary kidney function not reflected by GFRs. Secretion is rarely measured due to a paucity of validated markers. This study uses metabolomics to identify candidate endogenous solutes. Solutes were compared with the clearance of furosemide and penciclovir, two highly secreted medications, in 50 patients with and without CKD. Background: The proximal tubules eliminate protein-bound toxins and drugs through secretion. Measurements or estimates of GFR do not necessarily reflect the physiologically distinct process of secretion. Clinical assessment of this important intrinsic kidney function requires endogenous markers that are highly specific for secretory transport. Methods: We used metabolomics profiling to identify candidate markers of tubular secretory clearance in 50 participants from a kidney pharmacokinetics study. We measured metabolites in three sequential plasma samples and a concurrent 10-hour timed urine sample using hydrophilic interaction liquid chromatography/high-resolution mass spectrometry. We quantified the association between estimated kidney clearance and normalized plasma peak height of each candidate solute to the clearance of administered furosemide, a protein-bound, avidly secreted medication. Results: We identified 528 metabolites present in plasma and urine, excluding pharmaceuticals. We found seven highly (>50%) protein-bound and 49 poorly bound solutes with clearances significantly associated with furosemide clearance and 18 solute clearances favoring an association with furosemide clearance by the 90th percentile compared with GFR. We also found four highly bound and 42 poorly bound plasma levels that were significantly associated with furosemide clearance. Conclusions: We found several candidate metabolites whose kidney clearances or relative plasma levels are highly associated with furosemide clearance, an avidly secreted tracer medication of the organic anion transporters, highlighting their potential as endogenous markers of proximal tubular secretory clearance.