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Kidney Week

Abstract: PO0364

Quantitative Systems Toxicology (QST) Modeling of Drug-Induced Acute Proximal Tubule Epithelial Cell Injury and Associated Renal Hemodynamic Responses

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hamzavi, Nader, DILIsym Services, Inc., a Simulations Plus company, Research Triangle Park, North Carolina, United States
  • Gebremichael, Yeshitila, DILIsym Services, Inc., a Simulations Plus company, Research Triangle Park, North Carolina, United States
  • Woodhead, Jeffrey L., DILIsym Services, Inc., a Simulations Plus company, Research Triangle Park, North Carolina, United States
  • Ermakov, Sergey, DILIsym Services, Inc., a Simulations Plus company, Research Triangle Park, North Carolina, United States
  • Howell, Brett A., DILIsym Services, Inc., a Simulations Plus company, Research Triangle Park, North Carolina, United States
Background

Renal proximal tubule epithelial cells (RPTEC) are vulnerable to drug-induced toxicities which often result in acute kidney injury (AKI). Drug toxic effects range from mild sub-lethal RPTEC injuries to cellular death via multiple cellular damage mechanisms. At the systems level, decline in glomerular filtration rate (GFR) is a common manifestation of AKI. The complexity of pathophysiological responses (cellular, neurohormonal, hemodynamic) that lead to impaired filtration pose a challenge for reliable prediction of AKI. QST modeling is a promising method for translating cellular-level renal damage to clinical manifestations of AKI.

Methods

We developed RENAsym, a QST model of drug-induced AKI that includes key cellular injury mechanisms and renal hemodynamic responses. At the cellular level, RENAsym represents RPTEC life cycle, bioenergetics, and immune responses to renal toxicity. In vitro assays were used to parameterize key cellular injury mechanisms. At the systems level, RENAsym model represents renal function and feedback mechanisms including tubuloglomerular feedback (TGF) and renin-angiotensin-aldosterone systems (RAAS). RENAsym was employed to characterize the renal hemodynamic responses of drug induced RPTEC injury in humans treated with cisplatin.

Results

At the cellular level, urinary biomarkers such as KIM-1 and αGST were used to represent cellular injury and death following cisplatin exposure. RENAsym was able to capture the elevations in KIM-1 and αGST. The model also captured GFR decline and demonstrated that it occurs due to 1) increased Bowman’s pressure, 2) reduced intraglomerular pressure caused by vascular effects due to RAAS activation and TGF mechanisms, and 3) lower renal perfusion pressure from excess sodium and water excretion. The model quantitatively relates cellular injury and biomarker changes with renal hemodynamic responses.

Conclusion

RENAsym represents kidney function at cellular and organ levels in healthy and pathologic states caused by toxic drug effects. By describing drug induced cellular injury and subsequent hemodynamic changes it can predict clinical responses during AKI.

Funding

  • NIDDK Support