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Kidney Week

Abstract: PO2361

Reduction in Proximal Tubular Secretion Precedes Reduction in Glomerular Filtration Rate in the Adenine-Induced CKD Model

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1800 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Kougioumtzidou, Eleni, Astrazeneca, Gothenburg, Sweden
  • Miliotis, Tasso, Astrazeneca, Gothenburg, Sweden
  • Granqvist, Anna, Astrazeneca, Gothenburg, Sweden
  • Soderberg, Magnus, Astrazeneca, Gothenburg, Sweden
Background

Glomerular filtration rate (GFR) is frequently used to instruct dose levels of renally cleared drugs in patients with renal disease. This is based on the assumption that proximal tubule secretory clearance declines equally to GFR during disease progression. We tested this hypothesis in adenine-induced CKD mouse model.

Methods

C57BL/6 mice were fed either control or 0.2% adenine diet to induce progressive kidney damage. Body weight, urinary output, GFR and tubular secretion were monitored and histological analysis performed to assess disease progression at 1 and 3 weeks. Tubular secretion was estimated by measuring renal clearance of the endogenous secretory solutes indoxyl sulfate (IS), hippuric acid (HA) and cinnamoyglycine (CMG) using liquid chromatography couple to mass spectrometry. GFR was estimated by transcutaneous measurements.

Results

Mice on adenine diet developed kidney disease, indicated by progressive GFR decline. Histological assessment showed normal glomeruli throughout the study and a moderate tubular damage at 1 week which progressed to severe at 3 weeks. However, the maximum urinary albumin-creatinine ratio was reached already at 1 week of treatment, as was Kim-1, an early tubular injury marker, suggesting extensive early tubular injury and functional damage preceding structural damage. Likewise, when tubular secretion was assessed directly, a profound decrease in renal clearance of IS was detected already after 1 week on adenine diet with only a small further decrease by the 3rd week. Similar trends were observed for HA and CMG. In direct comparison, the decline in GFR versus tubular secretion over time revealed that at 1 week GFR was decreased by 30% whereas tubular secretion was decreased by >65%, suggesting earlier impact on the latter. Immunohistological analysis revealed a reduction in Oat1 transporter expression, to an extent not fully accounting for the reduction in secretion. This suggests a component of Oat1 inhibition and/or involvement of other transporters.

Conclusion

Our results indicate that tubular secretory function can be dissociated from glomerular filtration. Thus, assessment of tubular function based on GFR alone can be misleading, which has implications for dosing of renally excreted drugs to patients with kidney disease.

Funding

  • Commercial Support