Mechanism and reversal of drug-induced nephrotoxicity on a chip

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.

Glucose Metabolism in Acute Kidney Injury and Kidney Repair

“…We further demonstrated that the protective effect of canagliflozin in cisplatin-induced nephrotoxicity was related to decreased cisplatin uptake by renal tubular cells and the activation of the AKT pathway ( 74 ). In addition, Cohen et al used organ-on-chip models, vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, to achieve a dynamic assessment of cellular metabolism and verified that empagliflozin (another SGLT2 inhibitor) could block cisplatin toxicity in the kidneys by impeding glucose reabsorption ( 75 ). Despite these studies, the molecular mechanisms underlying the changes of glucose metabolism in cisplatin-induced AKI remain largely unknown.…”

Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism

“…The kidney is also vulnerable to injuries caused by numerous challenges such as ischemia [ 8 , 9 , 10 , 11 , 12 ], drug toxicity [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], environmental heavy metal exposure [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ], hypertension [ 28 , 29 , 30 ], immune injury [ 31 , 32 ], and diabetes [ 33 , 34 , 35 , 36 ]. In terms of environmental risk factors, human kidney disease caused by environmental pollutants and occupational-linked toxins is a major public health issue [ 37 ].…”

Drug toxicity in the proximal tubule: new models, methods and mechanisms

“…An example of a multimodal approach is provided by a recent study that identified multiple pathways altered by cisplatin in human-derived PT cells, including the Nrf2-mediated oxidative stress response, various mitochondrial processes, and AMPK, mTOR and p53 signaling [42]. Furthermore, deployment of tissue-embedded microsensors for oxygen and various metabolites in human kidney spheroids has revealed that glucose uptake is critical to the development of lipotoxicity induced by cyclosporine and cisplatin [43].…”