FROM TUBULAR TRANSPORT TO FIBROSIS: INDOXYL SULFATE AS A CANDIDATE BIOMARKER FOR KIDNEY TUBULAR FUNCTION

Abstract

Proximal tubular secretion is a key component of kidney function, yet it is underrepresented by current clinical markers. Indoxyl sulfate (IS), a protein-bound uremic toxin (PBUT) primarily cleared via tubular secretion, may serve as a sensitive marker of tubular function. In this study, we investigated IS concentrations and clearance in two mouse models of ischemia-reperfusion injury (IRI) representing chronic and acute kidney injury. Plasma, urine and kidney tissue concentrations of IS and 6 other PBUTs were measured by means by LC-MS/MS, and relevant influx (OAT1 and OAT3) and efflux (MRP4 and BCRP) transporter gene and protein expression was assessed by means of qPCR and Western Blot respectively. We found that IS accumulated in plasma after kidney injury, and IS clearance significantly decreased. They correlated better with interstitial fibrosis and tubular atrophy (IFTA%) scores than conventional kidney markers. We found that the transporters were downregulated after kidney injury both on a gene and protein expression level. IS was also found to accumulate in kidney tissue after post-IRI and positively correlated with IFTA scores and fibronectin gene expression. These findings suggest that IS reflects tubular injury and fibrosis better than conventional markers and may provide a less invasive means to assess tubulointerstitial damage.