Abstract: SA-PO915
Indoxyl Sulfate as Potential Kidney Tubular Function Marker across Kidney Disease Models
Session Information
- Pathology and Lab Medicine - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1800 Pathology and Lab Medicine
Authors
- Ahmed, Sabbir, Universiteit Utrecht, Utrecht, Utrecht, Netherlands
- Knoppert, Sebastiaan, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
- Harwood, Rachel V., University of Liverpool, Liverpool, United Kingdom
- Faria, João, Universiteit Utrecht, Utrecht, Utrecht, Netherlands
- Besseling, Paul J., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
- Sparidans, Rolf, Universiteit Utrecht, Utrecht, Utrecht, Netherlands
- Mihaila, Silvia M., Universiteit Utrecht, Utrecht, Utrecht, Netherlands
- Murray, Patricia, University of Liverpool, Liverpool, United Kingdom
- Nguyen, Tri Q., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
- Gerritsen, Karin G., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
- Masereeuw, Rosalinde, Universiteit Utrecht, Utrecht, Utrecht, Netherlands
Background
Kidney tubular damage is a strong predictor of end-stage kidney disease (ESKD) progression. Tubular function involves active secretion via transporters, such as organic anion transporters (OATs), to eliminate waste and metabolites, including protein bound uremic toxins (PBUTs). In tubular dysfunction, PBUT accumulation has been associated with many ESKD comorbidities. We hypothesized that PBUTs may be used as sensitive markers for tubular dysfunction.
Methods
We evaluated this in experimental models of chronic (rat nephrectomy and mouse IRI) and acute (mouse and in vitro IRI) kidney disease.
Results
In rats, PBUT parameters correlated with urinary tubular injury markers (kidney injury molecule-1 (Kim-1; p<0.001), neutrophil gelatinase-associated lipocalin (NGAL; p= 0.965 to <0.001), Beta-2-microglobuline (B2M; p<0.001) and cystatin C (p<0.001)). Moreover, indoxyl sulfate (IS) correlated better in a subgroup with the lowest tubular injury (p= 0.06 to <0.05) than filtration markers (GFR and plasma creatinine, cystatin C and urea (p= 0.54 to 0.07)). In chronic IRI mice, plasma IS and its clearance correlated with tubular atrophy scores, plasma NGAL and NGAL excretion (p<0.05 to <0.001), whereas filtration markers did not correlate. In acute IRI mice, IS and hippuric acid (HA) clearance correlated with plasma NGAL (p=0.058). Among all PBUTs, IS parameters showed the most consistent correlations with tubular injury markers across the animal models. Furthermore, proximal tubule transporters Oat1/3 expression was downregulated in mouse models and correlated with PBUT parameters. In agreement, OAT1-mediated transport of IS was decreased after inducing IRI in vitro using a human kidney proximal tubule cell line.
Conclusion
Our findings suggest that plasma IS and its clearance represent kidney transporters-related tubular function and may serve as sensitive clinical biomarkers for tubular dysfunction in kidney diseases.
Funding
- Private Foundation Support