Method Profile
Measure time-dependent human proximal tubule injury and couple biomarker shedding to simulated renal drug exposure.
Investigate acute and sustained nephrotoxic responses and explore conditional translation of KIM-1 profiles.
Perfused three-dimensional primary human proximal tubules from donor HIM-31; static two-dimensional culture from the same source; separate whole-body PBPK and biomarker QSP models.
Nortis HARV-1 chip with 0.5 μL/min perfusion; two- or ten-day exposure to cisplatin, rifampicin or gentamicin; early six-/24-hour and subsequent 48-hour biomarker sampling.
Experimental comparison
Estimated 5,000 cells per chip and 10,000 per static well; measurements start eight days after seeding; KIM-1 kinetics and PrestoBlue metabolic activity measured on days 0 and 10 are interpreted together.
Computational translation
Exposure interpolation, nephron-number scaling and a separately modeled neutrophil effect based on mouse recruitment and cell-model shedding data.
Relate concentration-dependent biomarker shedding to population-PBPK exposure and scale to kidney size. Distinguish observed experimental injury from modeled immune amplification; interpret low KIM-1 with viability and time since exposure.
Three-drug chip/static comparison, duration comparison and retrospective clinical biomarker-profile comparison.
One primary-cell donor; estimated 5,000 chip/10,000 static cells per culture. Separate population model simulated 100 virtual patients.
Untreated cultures, static two-dimensional cultures, two- versus ten-day exposure, models with versus without immune effects and published clinical KIM-1 profiles.
Untreated chip KIM-1 was about tenfold lower than static baseline. All tested conditions increased chip KIM-1 at six hours; later decreases could accompany metabolic-activity loss or occur without it. Adding an assumed immune component produced simulated cisplatin/rifampicin plasma peaks around 1,000 pg/mL at 12–24 hours.
A 2019 study paired human proximal tubule chips with pharmacokinetic and biomarker models. Early KIM-1 increases captured drug injury, while later decreases had different meanings across conditions; modeled immune effects helped extend the short-lived chip signal toward reported clinical profiles.
