Efentakis Panagiotis, Lamprou Sofia, Makridakis Manousos, Barla Ioanna, Nikolaou Panagiota-Efstathia, Christodoulou Andriana, Dimitriou Costantinos, Kostomitsopoulos Nikolaos, Ntanasis-Stathopoulos Ioannis, Theochari Irene, Gavriatopoulou Maria, Gakiopoulou Harikleia, Tasouli Androniki, Vlahou Antonia, Gikas Evangelos, Thomaidis Nikolaos, Dimopoulos Meletios-Athanasios, Terpos Evangelos, Andreadou Ioanna
Laboratory of Pharmacology, School of Pharmacy, National and Kapodistrian University of Athens, Greece.
Biomedical Research Foundation Academy of Athens, Greece.
Hemasphere. 2022 Oct 18;6(11):e791. doi: 10.1097/HS9.0000000000000791. eCollection 2022 Nov.
Carfilzomib is an irreversible proteasome inhibitor indicated for relapsed/refractory multiple myeloma. Carfilzomib toxicity includes renal adverse effects (RAEs) of obscure pathobiology. Therefore, we investigated the mechanisms of nephrotoxicity developed by Carfilzomib. In a first experimental series, we used our previously established in vivo mouse models of Carfilzomib cardiotoxicity, that incorporated 2 and 4 doses of Carfilzomib, to identify whether Carfilzomib affects renal pathways. Hematology and biochemical analyses were performed, while kidneys underwent histological and molecular analyses. In a second and third experimental series, the 4 doses protocol was repeated for 24 hours urine collection and proteomic/metabolomic analyses. To test an experimental intervention, primary murine collecting duct tubular epithelial cells were treated with Carfilzomib and/or Eplerenone and Metformin. Finally, Eplerenone was orally co-administered with Carfilzomib daily (165 mg/kg) in the 4 doses protocol. We additionally used material from 7 patients to validate our findings and patients underwent biochemical analysis and assessment of renal mineralocorticoid receptor (MR) axis activation. In vivo screening showed that Carfilzomib-induced renal histological deficits and increased serum creatinine, urea, NGAL levels, and proteinuria only in the 4 doses protocol. Carfilzomib decreased diuresis, altered renal metabolism, and activated MR axis. This was consistent with the cytotoxicity found in primary murine collecting duct tubular epithelial cells, whereas Carfilzomib + Eplerenone co-administration abrogated Carfilzomib-related nephrotoxic effects in vitro and in vivo. Renal SGK-1, a marker of MR activation, increased in patients with Carfilzomib-related RAEs. Conclusively, Carfilzomib-induced renal MR/SGK-1 activation orchestrates RAEs and water retention both in vivo and in the clinical setting. MR blockade emerges as a potential therapeutic approach against Carfilzomib-related nephrotoxicity.
卡非佐米是一种不可逆的蛋白酶体抑制剂，适用于复发/难治性多发性骨髓瘤。卡非佐米的毒性包括发病机制不明的肾脏不良反应（RAEs）。因此，我们研究了卡非佐米引起肾毒性的机制。在第一个实验系列中，我们使用了先前建立的卡非佐米心脏毒性体内小鼠模型，该模型采用2剂和4剂卡非佐米，以确定卡非佐米是否影响肾脏通路。进行了血液学和生化分析，同时对肾脏进行了组织学和分子分析。在第二个和第三个实验系列中，重复4剂方案以收集24小时尿液并进行蛋白质组学/代谢组学分析。为了测试一种实验性干预措施，用卡非佐米和/或依普利酮及二甲双胍处理原代小鼠集合管肾小管上皮细胞。最后，在4剂方案中，依普利酮与卡非佐米每日口服联合给药（165mg/kg）。我们还使用了7例患者的材料来验证我们的发现，患者接受了生化分析和肾盐皮质激素受体（MR）轴激活评估。体内筛选显示，仅在4剂方案中，卡非佐米会导致肾脏组织学缺陷，并增加血清肌酐、尿素、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）水平和蛋白尿。卡非佐米减少利尿，改变肾脏代谢，并激活MR轴。这与在原代小鼠集合管肾小管上皮细胞中发现的细胞毒性一致，而卡非佐米与依普利酮联合给药在体外和体内消除了与卡非佐米相关的肾毒性作用。在与卡非佐米相关的RAEs患者中，肾特异性蛋白激酶-1（SGK-1）（MR激活的标志物）增加。总之，卡非佐米诱导的肾MR/SGK-1激活在体内和临床环境中均导致RAEs和水潴留。MR阻断成为对抗卡非佐米相关肾毒性的一种潜在治疗方法。
