Mechanism and Reversal of Nephrotoxicity on a Chip

The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that particularly vulnerable to drug-induced nephrotoxicity. Here we introduce a model of vascularized human kidney organoids with integrated tissue embedded micro-sensors for oxygen, glucose, lactate and glutamine, providing real time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporin (Neoral®) and the anti-cancer drug cisplatin (Platinol®) disrupt proximal tubule polarity at sub-toxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporin and cisplatin toxicity by 1,000 to 10-folds, respectively. Retrospective study of 247 patients receiving cyclosporin or cisplatin in combination with the SGLT-2 inhibitor gliflozin showed significant reduction in creatinine and uric acid recognized markers of kidney damage. These results demonstrate the potential of sensor-integrated organoid-on-chip platforms to elucidate new mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures. Overall design: Comparison between different proximal tubule in vitro models