Organ-on-Chip analysis of kidney metabolism reveals glucose-driven lipotoxicity as a mechanism of drug-induced nephrotoxicity

The kidney is an essential organ tasked with glucose and fluid homeostasis, detoxification, and excretion of toxic metabolites and drugs. Approximately 20% of nephrotoxicity is induced by drugs, but medication of the elderly increases the incidence of nephrotoxicity up to 66% as the average life span increases. Because renal tubules, especially proximal tubule cells, are exposed to drugs in the process of concentration and reabsorption through the glomerulus, they are influenced greatly by drug toxicity. Cytotoxicity occurs due to the damaged mitochondria in tubules, the disturbed tubular transport system, and the increase in oxidative stress by free radical generation.

We developed a novel platform bearing mature polarized human kidney organoids with three-dimensional longitudinal tubule-like structures. These organoids are embedded with micro-sensors and cultured in perfused bioreactors enabling real-time measurements of their oxygen consumption. Perfusion outputs are fluidically linked to electrochemical sensors for direct measurements of key metabolites in central carbon metabolism. We perform a metabolic flux analysis to characterize how these organoids shift their metabolism over time while they are continuously exposed to different drugs. Based on experiments done in this model we revealed that Cisplatin, Cyclosporin A and Gentamicin induced nephrotoxicity is mediated by glucose-driven lipid accumulation and adverse outcomes could be reduced with SGLT2 inhibitors. Thus, we aim to show retrospectively that patients treated with SGLT2 inhibitors, develop lower nephrotoxicity and adverse reactions to Cisplatin and Cyclosporin A treatments.