Implementation of Drug‐Induced Rhabdomyolysis and Acute Kidney Injury in Microphysiological System

Abstract

Rhabdomyolysis, the breakdown of musculoskeletal tissue, can lead to life-threatening complications such as rhabdomyolysis-induced acute kidney injury (RI-AKI), in which drug-induced cases being the most common. Given the variability in the severity of drug-induced adverse effects among patients, the development of a patient-specific in vitro drug testing model to pre-emptively assess the impact of drugs on muscle and kidney function is of paramount importance in order to mitigate the potential for harm. However, the lack of models that accurately mimic the interactions between muscles and kidneys, along with the limited accessibility of existing models, poses a significant challenge for the effective study of rhabdomyolysis and RI-AKI. To address this issue, this work develops a 3D muscle-kidney proximal tubule-on-a-chip (MKoaC) platform that cocultures musculoskeletal tissue with kidney epithelium. This system enables straightforward, flexible control of the coculture period, facilitating enhanced muscle growth and function while preserving kidney viability. Following treatment with atorvastatin and fenofibrate, the MKoaC successfully mimicked drug-induced rhabdomyolysis and acute kidney injury (AKI), with atorvastatin exhibiting higher toxicity than fenofibrate. The MKoaC serves as a robust platform for studying drug toxicity and tissue interactions, advancing preclinical drug screening and therapeutic strategies for rhabdomyolysis and AKI.