Research ArticleDRUG TESTING

Mechanism and reversal of drug-induced nephrotoxicity on a chip

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Science Translational Medicine  24 Feb 2021:
Vol. 13, Issue 582, eabd6299
DOI: 10.1126/scitranslmed.abd6299

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Chipping away at nephrotoxicity

Tissue-on-a-chip technology can help elucidate mechanisms of drug-induced toxicity. Here, Cohen et al. used vascularized human kidney spheroids-on-a-chip and embedded sensors to monitor cellular metabolism in response to drug treatments. They found that proximal tubule polarity was disrupted and toxicity resulted from glucose accumulation upon exposure to cyclosporine and cisplatin, which could be prevented by inhibiting glucose reabsorption. Glomerular filtration rates were higher and markers of kidney damage were lower in patients treated with cyclosporine or cisplatin in combination with a sodium-glucose cotransporter-2 inhibitor. This study demonstrates the utility of kidney spheroid-on-a-chip technology to study mechanisms of drug-induced nephrotoxicity.

Abstract

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 is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures.

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