- Novel Acute kidney injury (AKI) biomarkers enhance disease understanding and aid timely interventions.
- N-acetyl-beta-D-glucosaminidase (NAG) is a novel biomarker which is released in the urine due to proximal tubular damage¹.
- While elevated levels of NAG in urine have been associated with renal tubular cell breakdown, the mechanistic underpinnings of NAG release remain poorly understood.
The aim of this study is to investigate the relationship between NAG release and
potential mechanisms of proximal tubular injury, and to identify a responsible mechanism to guide NAG release during AKI.
- 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 or sublethal injury in the form of brush border loss.
- In RENAsym, ATP decline results in various forms of cellular injury including
microfilament disruption, brush border loss 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 cisplatin² and Cyclosporine A (CsA)³.
- Data shows that urinary NAG (uNAG) peaked on day 5 in rats treated with 5 mg/kg cisplatin²
- In our model, when uNAG release is connected to microfilament disruption, simulated uNAG peaks around day 10 with a slow decay post-treatment with 5 mg/kg cisplatin
- However, when uNAG release is driven by necrosis, simulated uNAG peak time occurs on day 5 consistent with observations
- The model was then calibrated to AstraZeneca’s biomarker data instead of uNAG in cisplatin-induced AKI rats
- Simulated uNAG peak time occurs on day 5 or 6 with maintained elevation until day 14 after administration of daily dosing of CsA into rats for two weeks
- Predicted uNAG for rats treated with 5 mg/kg cisplatin with the optimized model is within the wide range of observed data³,⁶-⁷ peaked on day 4 and resolved within 48-72 hours
- In this urinary NAG release model, cellular necrosis is found to be the correct
mechanism to drive NAG release, and to successfully reproduce the NAG time course during drug-induced AKI.
- The model could recapitulate the timing of observed NAG levels in cisplatin-induced injury in rats, and NAG kinetics in CsA-induced injury in rats.
- High mortality rate in rats treated with 5 mg/kg cisplatin raises doubts in biomarker data collected after day 5 post-treatment with cisplatin.
- A virtual population model can effectively capture interpatient variability by varying
and combining pathophysiologic parameters across a spectrum of baseline individuals.
By Nader Hamzavi, Pallavi Bhargava, Simone H. Stahl, Brett A. Howell, and Jeffrey L. Woodhead
American Society of Nephrology Kidney Week, November 1-5, 2023, Philadelphia, PA