HemaSphere (Nov 2022)

Mineralocorticoid Receptor Pathway Is a Key Mediator of Carfilzomib-induced Nephrotoxicity: Preventive Role of Eplerenone

  • Panagiotis Efentakis,
  • Sofia Lamprou,
  • Manousos Makridakis,
  • Ioanna Barla,
  • Panagiota-Efstathia Nikolaou,
  • Andriana Christodoulou,
  • Costantinos Dimitriou,
  • Nikolaos Kostomitsopoulos,
  • Ioannis Ntanasis-Stathopoulos,
  • Irene Theochari,
  • Maria Gavriatopoulou,
  • Harikleia Gakiopoulou,
  • Androniki Tasouli,
  • Antonia Vlahou,
  • Evangelos Gikas,
  • Nikolaos Thomaidis,
  • Meletios-Athanasios Dimopoulos,
  • Evangelos Terpos,
  • Ioanna Andreadou

DOI
https://doi.org/10.1097/HS9.0000000000000791
Journal volume & issue
Vol. 6, no. 11
p. e791

Abstract

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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.