Kidney Week

Abstract: TH-PO046

Identifying a Potential New Weapon against AKI in Cisplatin-Treated Patients

Session Information

• AKI: Epidemiology, Risk Factors, and Prevention - 1
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 101 AKI: Epidemiology, Risk Factors, and Prevention

Authors

• Valiño Rivas, Lara, Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón., Madrid, Madrid, Spain

Lara Valiño Rivas, PhD

• Gonzalez-Nicolas Gonzalez, Maria Angeles, Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón., Madrid, Madrid, Spain

Maria Angeles Gonzalez-Nicolas Gonzalez, PhD

• Moreno-Gordaliza, Estefanía, Department of Analytical Chemistry, Faculty of Chemistry, Universidad Complutense de Madrid., Madrid, Madrid, Spain

Estefanía Moreno-Gordaliza, PhD

• Ogando, Elena Vázquez, Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón., Madrid, Madrid, Spain

Elena Vázquez Ogando, MBA

• Gómez-Gómez, Milagros, Department of Analytical Chemistry, Faculty of Chemistry, Universidad Complutense de Madrid., Madrid, Madrid, Spain

Milagros Gómez-Gómez, PhD

• Lazaro Fernandez, Alberto, Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón., Madrid, Madrid, Spain

Alberto Lazaro Fernandez, PhD

Background

Cisplatin is a highly effective chemotherapeutic agent, widely used in clinical practices against a large number of tumors, whose common side effect limiting its dose-duration of treatment is Acute Kidney Injury (AKI). Cisplatin-AKI is associated with a high morbidity and mortality rate and currently, there is no effective treatment for it. ALME23 (under intellectual property rights protection) is an organic anion transporters (OATs) inhibitor used at the clinical level for which some old scientific studies suggested a link with nephroprotection in AKI. In this study, we investigated in vitro a potential new drug against cisplatin-induced AKI.

Methods

Human proximal tubular cells (HK2) were treated with cisplatin in the presence or absence of ALME23. Apoptosis was assessed by MTT, direct microscopic observation and flow-cytometry. Apoptotic mediator’s levels of the intrinsic (mitochondrial) and extrinsic (death receptor) apoptotic pathways were measured by confocal microscopy, Western Blot and JC-1 assay. Cell regeneration was also assessed by crystal violet. Some tumor cisplatin-target lines were also used to evaluate cisplatin tumorigenic activity in presence of ALME23. Intracellular accumulation of cisplatin was measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Inflammation was also measured at early stages of AKI by RT-qPCR.

Results

Our results suggested that ALME23 seems to protect HK2 cells against cisplatin-induced apoptosis and both the intrinsic and extrinsic pathway, promoting cell regeneration. Furthermore, ALME23 resulted harmless to the cells without affecting their growth and viability, nor does it affect the chemotherapeutic activity of cisplatin in tumor lines, protecting them in an organ-specific manner. Cotreatment of cisplatin with ALME23 also reduced inflammatory damage in early stages of cisplatin-AKI. Regarding the mechanism of action, some of these protective effects may be due to the fact that it partially prevents cisplatin from entering the cell.

Conclusion

This study provides evidence that ALME23 could be a new therapeutic alternative to nephrotoxicity in cisplatin-treated patients without compromising its chemotherapeutic efficacy. However, studies in animal models and later in humans, will be required.

Funding

• Government Support – Non-U.S.