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Kidney Week

Abstract: PO0411

Mechanistic Modeling of Kidney-Injury Molecule 1 (KIM-1) as a Biomarker for Cisplatin-Induced AKI

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

Kidney Injury Molecule 1 (KIM-1) is a specific and sensitive biomarker for drug-induced acute kidney injury (AKI) prediction. Cisplatin-induced injury of the renal proximal tubular epithelial cells (RPTEC) has been characterized using KIM-1 in both in vivo and in vitro studies. Despite growing interest in clinical use of KIM-1 as a key biomarker for AKI diagnosis, a mechanistic model of KIM-1 that accurately predicts the kinetics of KIM-1 is still lacking. We developed a mechanistic model of KIM-1 as part of a quantitative systems toxicology (QST) model to predict urinary KIM-1 in rats treated with cisplatin.

Methods

We developed a mechanistic model of KIM-1 within the framework of RENAsym, a QST model of drug-induced AKI that incorporates key cellular injury mechanisms and renal hemodynamics. The KIM-1 model represents the early shedding of KIM-1 arising from the loss of brush borders during sub-lethal injury of RPTEC followed by the marked expression of KIM-1 in dedifferentiated cells in regenerating proximal tubules (Ichimura et al. 1998). The model is integrated with the RENAsym to capture RPTEC injury and regeneration following toxic renal injury.

Results

RENAsym was used to simulate the response of urinary KIM-1 in rats treated with cisplatin. The model parameters were fitted to data from rats treated with 2.5 mg/kg cisplatin (Gebremichael et al. 2017). The magnitude and time profile of KIM-1 were captured by the model. The KIM-1 model was also analyzed using data obtained from rats treated with single doses of 1 and 5mg/kg of cisplatin, and it can recapitulate the dose-dependent responses of urinary Kim-1.

Conclusion

Mechanistic model of KIM-1 was developed to quantitatively predicted cisplatin-induced AKI. The model recapitulated the urinary KIM-1 data obtained from rats treated with cisplatin. Human data will be used in the future for model validation.

Funding

  • NIDDK Support