Nephrotoxicity Associated with the Combination of Cisplatin and Immune Checkpoint Inhibitors. Histopathological Study
Abstract The introduction of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1) as targeted therapies (immunotherapy) has improved the efficacy and safety profile of cancer treatments. However, they are not free of adverse effects, including renal injury. The aim of this work was the histological evaluation of renal damage associated with anti-CTLA-4 and anti-PD-1 in combination with cisplatin in a murine model. An experimental model was designed in C57BL/6 mice treated with combined anti-CTLA-4 and anti-PD-1 therapy, as well as combined triple therapy of anti-CTLA-4, anti-PD-1 and cisplatin. Groups treated with the drug monotherapies and a control group were also included. After sacrifice (day 6), renal histological sections were performed and stained with haematoxylin-eosin. Histological renal damage assessment was performed in a blinded fashion following a tissue injury quantification protocol based on a numerical scale. The data obtained were analysed using SPSS statistical software. The results showed significant renal tubular damage associated with the combined therapy of cisplatin with anti-CTLA-4 and anti-PD-1, the latter enhancing the damage produced by cisplatin monotherapy. This model will allow us to investigate the mechanisms of toxicity involved, as well as to identify possible urinary biomarkers associated with the renal damage produced by these therapies.
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Rassy EE, Bakouny Z, Yared F, Chelala DN, Karak FE, Ghosn M. The nephrotoxicity of immune checkpoint inhibitor–based combinations. Eur J Cancer. 2018;103:274-8.
Ricaurte Sarabia M, Villalobos J. Efecto nefrotóxico causado por cisplatino mediante su acumulación a través de proteínas transportadoras. Vitae Acad Bioméd Digit. 2019;(78):3.
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51-60.
Spiers L, Coupe N, Payne M. Toxicities associated with checkpoint inhibitors–an overview. Rheumatology. 2019;58(Supplement 7) 7-16.
Vasquez L, Castro D, León J de, Beltrán B. Inmunoterapia en cáncer: de los inicios al premio Nobel. Rev Peru Med Exp Salud Pública. 2020;37:115-21.
Welsh J, Paul. D. What to Know About Adjuvant Therapies [Internet]. Verywell Health. 2021 [citado 7 abr. 2023]. Disponible en: https://www.verywellhealth.com/adjuvant-therapy-5198903
Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin Nephrotoxicity: A Review. Am J Med Sci. 2007;334(2):115-24.
Abril A, Tascón J, Vicente-Vicente L, Casanova AG, Prieto M, Morales AI. Caracterización funcional del daño renal asociado a la inmunoterapia oncológica. FarmaJournal. 2023;8(1):7-19.
Alonso F, Martín de Francisco ÁLM, Auñón P, García-Carro C, García P, Gutiérrez E et al. Efectos renales adversos por inhibidores del check-point (ICP) en pacientes con cáncer. Recomendaciones del grupo de Onconefrología de la Sociedad Española de Nefrología (SEN). Nefrología [Internet]. [citado 8 may. 2023]. Disponible en: http://www.revistanefrologia.com/es-efectos-renales-adversos-por-inhibidores-avance-S0211699522001990
Calderón-Ospina CA, Guzmán-Ramírez GM, Sarmiento-Monroy JC, Gómez-Angulo DL, Joya-Higuera AY, Ríos-Barajas LF et al. Nefrotoxicidad inducida por medicamentos. Médicas UIS [Internet]. 26 de abril de 2011 [citado 6 abr. 2023];24(1). Disponible en: https://revistas.uis.edu.co/index.php/revistamedicasuis/article/view/2583
Darvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Exp Mol Med. 2018;50(12):1-11.
Dumoulin DW, Visser S, Cornelissen R, van Gelder T, Vansteenkiste J, von der Thusen J et al. Renal Toxicity from Pemetrexed and Pembrolizumab in the Era of Combination Therapy in Patients with Metastatic Nonsquamous Cell NSCLC. J Thorac Oncol. 2020;15(9):1472-83.
López JM, Ensuncho AE, Robles J. Estudio Teórico de la Reactividad Química y Biológica de Cisplatino y algunos Derivados con Actividad Anticancerosa. Inf Tecnológica. 2013;24(3):3-14.
Méndez JDM, Hernández JSC, Plazas WDE, López EFB. Nefrotoxicidad por cisplatino en pacientes de la unidad de cancerología del Hospital Universitario Hernando Moncaleano Perdomo de Neiva. RFS Rev Fac Salud. 2014;6(2):39-44.
Rassy EE, Bakouny Z, Yared F, Chelala DN, Karak FE, Ghosn M. The nephrotoxicity of immune checkpoint inhibitor–based combinations. Eur J Cancer. 2018;103:274-8.
Ricaurte Sarabia M, Villalobos J. Efecto nefrotóxico causado por cisplatino mediante su acumulación a través de proteínas transportadoras. Vitae Acad Bioméd Digit. 2019;(78):3.
Spain L, Diem S, Larkin J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev. 2016;44:51-60.
Spiers L, Coupe N, Payne M. Toxicities associated with checkpoint inhibitors–an overview. Rheumatology. 2019;58(Supplement 7) 7-16.
Vasquez L, Castro D, León J de, Beltrán B. Inmunoterapia en cáncer: de los inicios al premio Nobel. Rev Peru Med Exp Salud Pública. 2020;37:115-21.
Welsh J, Paul. D. What to Know About Adjuvant Therapies [Internet]. Verywell Health. 2021 [citado 7 abr. 2023]. Disponible en: https://www.verywellhealth.com/adjuvant-therapy-5198903
Yao X, Panichpisal K, Kurtzman N, Nugent K. Cisplatin Nephrotoxicity: A Review. Am J Med Sci. 2007;334(2):115-24.
Ausin, J., Tascón, J., Casanova, A. G., Vicente-Vicente, L., Morales, A. I., & Prieto, M. (2024). Nephrotoxicity Associated with the Combination of Cisplatin and Immune Checkpoint Inhibitors. Histopathological Study. FarmaJournal, 9(1), 7–17. https://doi.org/10.14201/fj202491717
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