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Mar 27, 2022
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Modeling of Cyclosporine A-Induced Acute Kidney Injury with RENAsym®

Background

Cyclosporine A (CsA) is an immunosuppressant commonly used to prevent organ rejection and can be used to treat other diseases such as rheumatoid arthritis, atopic dermatitis, and psoriasis¹. However, the use of CsA can cause tubular damage leading to a decline in renal function as indicated by increases in serum creatinine levels and decreases in glomerular filtration rate (GFR)². Low (2-8mg/kg) and high (10-17mg/kg) doses have the potential to cause lasting renal injury¹. This work uses RENAsym, a quantitative systems toxicology (QST) model of acute kidney injury (AKI), to recapitulate clinical outcomes following low and high dose CsA administration in humans.

Methods

To define to the potential for CsA-induced nephrotoxicity, the effects of CsA on mitochondrial function and reactive oxygen species (ROS) production were determined. Human renal proximal tubule epithelial cells (RPTECs) were treated with CsA and its effects on mitochondrial respiration as well as ROS production were measured. The Seahorse XFe96 Analyzer (Agilant, Santa Clara, CA) was used to measure mitochondrial respiration and high content screening was used to measure ROS production after RPTECs were exposed to dihydroethidium staining.

These in vitro data were used to determine kidney toxicity parameters for use in RENAsym. CsA inhibited the mitochondrial election transport chain flux and induced ROS production. Together with these kidney toxicity parameters and with physiologically-based pharmacokinetic (PBPK) simulations of low and high clinical CsA exposures, created in GastroPlus®, kidney injury was predicted in RENAsym.

Results

RENAsym predicted CsA-induced kidney injury such as a decrease in kidney average ATP when simulated with 4mg/kg administration for 24 hours. CsA administration, 4mg/kg, was simulated for 6 months in RENAsym where an average of 1.5 to 3% decrease in GFR and a 1.5 to 2.5% increase in serum creatinine was predicted in a simulated population (SimPops™) consisting of N=267 individuals. Moreover, a 17mg/kg QD treatment for 3 months followed by 10mg/kg QD for another 3 months, was also simulated in RENAsym for 6 months where an average of 4 to 7% decrease in GFR and a 4 to 6% increase in serum creatinine was predicted in the same SimPops.

Conclusions

These data show qualitative agreement with clinical studies of CsA administration showing a decline in renal function³,⁴, however further refinement of this representation is underway for RENAsym v2A. This work shows the potential for RENAsym to accurately predict clinical outcomes and nephrotoxicity for future compounds.

References

  1. Bennet, William M., DeMattos, Angelo., Meyer, Mary M., Andoh, Takeshi., & Barry, John M. Chronic cyclosporine nephropathy: The Achilles’ heel of immunosuppressive therapy. Kidney International. 50, 1089-1100 (1996)
  2. Schaft, J., Zuilen, A., Deinum, J., Bruijnzeel-Koomen, C. & Bruin-Weller, M. Serum Creatinine Levels During and After Long-term Treatment with Cyclosporine A in Patients with Severe Atopic Dermatitis. Acta Derm. Venereol. 95, 963–967 (2015)
  3. Bagnis, C., Du Montcel S, Beaufils H, Jouanneau C, Jaudon M, Maksud P, Mallet A, Lehoang P, Deray G. Long-term Renal effect of Low-Dose Cyclosporine in Uveitis-treated Patients: Follow-up Study. JASN. 13, 2962-2968 (2002)
  4. Klintmalm, G., Sundfi. In B, Bohman, So., & Wilczek, H. Interstitial fibrosis in renal allografts after 12 to 46 months of cyclosporin treatment: Beneficial effect of low doses in early post-transplantation period. Lancet 2, 950-954 (1984)
  5. Kawait R., Mathew D, Tanaka C, & Rowland M. Physiologically Based Pharmacokinetics of Cyclosporine A: Extension to Tissue Distribution Kinetics in Rats and Scale-up to Human. JPET. 287 (2) 457-568 (1998)

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

Presented at Society of Toxicology (SOT) 61st Annual Meeting and ToxExpo, March 27-31, 2022

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