Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Sci Transl Med. 2021 Feb 24;13(582). doi: 10.1126/scitranslmed.abd6299.
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 ( < 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.
肾脏在体液平衡、葡萄糖控制和药物排泄方面发挥着关键作用。由于药物引起的肾毒性导致的肾功能丧失影响了超过 20%的成年人群。肾脏近端小管是一种复杂的血管化结构，特别容易受到药物引起的肾毒性的影响。在这里，我们引入了一种带有嵌入式组织微传感器的血管化人类肾脏球体模型，用于实时评估细胞代谢。我们的模型表明，免疫抑制剂环孢素和抗癌药物顺铂在亚毒性浓度下破坏近端小管极性，导致葡萄糖积累和脂毒性。使用葡萄糖转运抑制剂阻止葡萄糖重吸收，可分别使环孢素和顺铂的毒性降低 1000 至 3 倍。对 247 名接受环孢素或顺铂联合钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂恩格列净治疗的肾损伤患者进行的回顾性研究表明，肾功能显著改善（<0.001），同时肌酐和尿酸（肾损伤标志物）降低。这些结果表明，传感器集成的肾芯片平台具有阐明作用机制和快速重新制定有效治疗方案的潜力，从而提高药物安全性并降低临床和商业失败的成本。
