Abstract

Objectives:

The use of Cyclosporine A (CsA) can cause tubular damage leading to a decline in renal function as determined by decreases in serum creatinine levels, glomerular filtration rate (GFR), and ATP1. This work uses RENAsym®, a quantitative systems toxicology (QST) model of acute kidney injury (AKI), to recapitulate clinical outcomes following CsA administration in humans.

Methods:

The effects of CsA on mitochondrial function and reactive oxygen species (ROS) production were assessed to define the potential for CsA-induced kidney injury. Human renal proximal tubule epithelial cells (RPTECs) were treated with CsA and its effects on mitochondrial respiration as well as ROS production were measured. Seahorse XF96 Analyzer was used to measure mitochondrial respiration. High content screening was used to measure ROS production after RPTECs were exposed to dihydroethidium staining. These in vitro data were used to define kidney toxicity parameters, and together with PBPK simulations of clinical CsA exposure created in GastroPlus®, kidney injury was predicted in RENAsym.

Results:

CsA inhibited the mitochondrial election transport chain flux (ETC inhibition coefficient=1458.33μmol/L) and induced ROS production (Vmax=0.049 1/hr, Km =13.075 μmol/L). RENAsym predicted CsA-induced kidney injury such as a decrease in kidney average ATP as shown in Figure 4. RENAsym was further utilized to perform a mechanistic analysis to determine the main driver in simulated CsA nephrotoxicity. The mechanistic analysis indicated that CsA-induced kidney injury is primarily driven by inhibiting mitochondrial function via inhibition of the electron transport chain.

Conclusion:

Using in vitro data to determine toxicity parameters, RENAsym accurately predicted CsA- induced nephrotoxicity in humans, consistent with observations from clinical studies.

Presented at ACoP 11 Virtual Conference, Nov. 9-13, 2020

By Pallavi Bhargava, Christina Battista, Viera Lukacova, Jeffrey L. Woodhead