A human iPSC-derived kidney-liver organ-on-a-chip platform for modeling inter-organ crosstalk.

The liver and kidneys are essential for drug metabolism and clearance and are highly sensitive to toxicity. Most in vitro models assess these organs in isolation, limiting the study of inter-organ interactions. Here, an induced pluripotent stem cell (iPSC)-derived kidney-liver organ-on-a-chip model was developed that co-cultured hepatocyte-like cell (HLC) organobodies and proximal tubular-like cells (PTL) under microfluidic flow. In parallel, a PTL-HepaRG spheroid co-culture model was established to investigate bioactivation of the prodrug ifosfamide. Co-culture induced distinct transcriptional responses in PTL and HLC, as revealed by gene set enrichment analysis. In PTL, co-culture with HepaRG enriched signaling and cell polarity pathways, while co-culture with HLC enhanced metabolic and transport-related programs. In HLC, co-culture with PTL affected intermediary metabolism, lipid processing, redox regulation, and plasma protein synthesis. The PTL-HepaRG model demonstrated bioactivation of ifosfamide into metabolite chloroacetaldehyde, highlighting the utility of these systems for studying human-relevant kidney-liver interactions and drug metabolism in vitro. However, the concentration of chloroacetaldehyde was too low to cause adverse effects in the renal tissue in the current setup.