Indoxyl sulfate as a potential tubular function marker across kidney disease models

Abstract

Kidney tubular damage is a strong predictor of chronic kidney disease progression. Tubular function involves nutrient reabsorption and active secretion via transporters, such as the organic anion transporters (OATs), to eliminate waste and metabolites, including protein-bound uremic toxins (PBUTs). In tubular dysfunction, PBUTs accumulate in plasma, which has been associated with many comorbidities. We hypothesized that PBUT plasma concentration and clearance are sensitive markers for tubular dysfunction. We evaluated this in experimental models of chronic [rat nephrectomy and mouse ischemia-reperfusion injury (IRI)] and acute (mouse and in vitro IRI) kidney disease. In 5/6th nephrectomy rats, plasma concentration and clearance of PBUTs correlated with urinary tubular injury markers [kidney injury molecule-1 (Kim-1), neutrophil gelatinase-associated lipocalin (NGAL), beta-2 microglobulin, and cystatin C] better than with filtration markers [glomerular filtration rate (GFR) and plasma creatinine, cystatin C, and urea]. Moreover, indoxyl sulfate (IS) plasma concentration and clearance correlated in the subgroup with the lowest tubular injury. In chronic IRI mice with mild to moderate injury, plasma IS and its clearance correlated with tubular atrophy scores, plasma NGAL, and NGAL excretion, whereas filtration markers did not correlate. In acute IRI mice, IS and hippuric acid clearance correlated with plasma NGAL. Moreover, mass spectrometry imaging analyses revealed higher cortical but lower medullary accumulation of IS in IRI mice kidneys compared with healthy controls, which was accompanied by a downregulation of proximal tubular transporters. After inducing IRI in vitro using a human kidney proximal tubule cell line, decreased OAT1-mediated transport of IS was confirmed. Together, these findings suggest that plasma IS and its clearance represent kidney transporter-related tubular function and may serve as sensitive clinical biomarkers for tubular dysfunction in kidney diseases.