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Abstract: TH-PO190

Protein-Bound Uremic Toxins as Biomarkers of Kidney Tubular Function in Murine Long-Term Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Ahmed, Sabbir, Universiteit Utrecht Utrechts Instituut voor Farmaceutische Wetenschappen, Utrecht, Utrecht, Netherlands
  • Sparidans, Rolf, Universiteit Utrecht Utrechts Instituut voor Farmaceutische Wetenschappen, Utrecht, Utrecht, Netherlands
  • Mihaila, Silvia M., Universiteit Utrecht Utrechts Instituut voor Farmaceutische Wetenschappen, Utrecht, Utrecht, Netherlands
  • Broekhuizen, Roel, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Goldschmeding, Roel, Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Nguyen, Tri Q., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands
  • Masereeuw, Rosalinde, Universiteit Utrecht Utrechts Instituut voor Farmaceutische Wetenschappen, Utrecht, Utrecht, Netherlands
  • Gerritsen, Karin G., Universitair Medisch Centrum Utrecht, Utrecht, Utrecht, Netherlands

Group or Team Name

  • Prof. Roos' group, Pharmacology
Background

Kidney tubular damage is an important prognostic determinant in diabetic nephropathy (DN). A vital homeostatic function of the proximal tubule is the excretion of waste products, including protein-bound uremic toxins (PBUTs) that are actively being secreted via organic anion transporters (OATs), but accumulate in plasma in kidney dysfunction. We hypothesize that plasma concentration and renal clearance of PBUTs may be sensitive tubular function markers.

Methods

Diabetes mellitus was induced in C57Bl/6 mice by streptozotocin, which resulted in histopathological and functional kidney tubular damage after 6 and 8 months. PBUTs in plasma, 24h urine and kidney tissue were measured by LC-MS/MS.

Results

Among the PBUTs with the highest OAT affinity (viz. IS, HA and KA), plasma concentrations were 1.7-, 2.4- and 1.9-fold higher (p=0.005, <0.001, 0.006) after 6 months and 1.9-, 2.4- and 2.2-fold higher (p<0.001, <0.001, <0.001) after 8 months in DN (Fig 1A-C), respectively. Their urinary excretions, normalized for plasma concentrations (i.e. a surrogate for clearance), were 2.4-, 5.4- and 2.3-fold lower (p=0.005, <0.001, 0.01) after 6 months and 2.3-, 1.6-, 2.1-fold lower (p=0.032, 0.017, 0.002) after 8 months in DN (Fig 1D-F) respectively. The plasma concentration and clearance of these PBUTs correlated stronger with tubular atrophy, f4/80 scores and tubular injury markers than conventional filtration markers.

Conclusion

Tubular function is compromised in murine long-term DN, and plasma concentration and clearance of IS, HA and KA may represent biomarkers of kidney tubular function in DN. Future studies should focus on validation of the novel biomarkers in other species and forms of CKD.

Plasma concentration of IS, HA and KA elevated (A-C), and clearance reduced in DN mice after 6 and 8 months (mean ± SEM). DN: diabetic nephropathy; IS: indoxyl sulfate; HA: hippuric acid; KA: kynurenic acid.