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Kidney Week

Abstract: TH-PO126

Mechanistic Representation of NAG Release in Renal Proximal Tubular Cellular Injury

Session Information

  • AKI: Mechanisms - I
    November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hamzavi, Nader, Simulations Plus Inc, Lancaster, California, United States
  • Bhargava, Pallavi, Simulations Plus Inc, Lancaster, California, United States
  • Stahl, Simone H., Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge, United Kingdom
  • Woodhead, Jeffrey, Simulations Plus Inc, Lancaster, California, United States
Background

N-acetyl-beta-D-glucosaminidase (NAG) is a novel biomarker for early detection of tubular injury in the event of acute kidney injury (AKI). While elevated levels of NAG in urine have been associated with renal tubular cell breakdown, the mechanistic underpinnings of NAG release remain poorly understood. In this study, we investigated the relationship between NAG release and potential mechanisms of proximal tubular injury.

Methods

We developed a mathematical model of NAG release from proximal tubule cells (PTCs) within the framework of RENAsym, a quantitative systems toxicology model of drug-induced AKI. The model was designed to represent urinary NAG increase as a result of cellular necrosis and brush border loss. In RENAsym, ATP decline results in various forms of cellular injury including microfilament disruption and cellular necrosis. NAG release was simulated using a driving signal from either necrosis or microfilament disruption and parameterized using observed urinary NAG in rats treated with cisplatin [1] and cyclosporine A (CsA) [2].

[1] Weichert-Jacobsen, K J et al. Cancer research vol. 59,14 (1999): 3451-3.
[2] Nephrotoxicity biomarker evaluation after repeat dose oral administration of cyclosporine A in male rats. AstraZeneca, 2007.

Results

The results of our mathematical model of the NAG response indicate that the kinetics of urinary NAG in rats treated with cisplatin and CsA can be predicted using cellular necrosis. The model correctly predicted the peak time of urinary NAG in rats after single dose of 5 mg/kg cisplatin with time to resolution of ~48 hours. Furthermore, the model could recapitulate the dose-dependent response of NAG release in rats treated daily with CsA for two weeks. Specifically, NAG peak time occurred on day 5 or 6 and levels remained elevated until day 14. Simulated urinary NAG was shown to saturate at CsA doses of 30 mg/kg and higher, in line with observed data.

Conclusion

We developed a mechanistic model of NAG release in connection with cellular necrosis. The model predicts NAG kinetics for CsA- and cisplatin-mediated AKI as a useful biomarker for monitoring tubular injury in (pre)clinical settings.

Funding

  • Commercial Support – RENAsym development is funded by the RENAsym Consortium, which includes Janssen, AstraZeneca, AbbVie, Servier, Merck KGA, Gilead, and GSK as current members.