Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression.

Autor: Martinez Valenzuela L; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain. lmartinezv@bellvitgehospital.cat., Gómez-Preciado F; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain., Guiteras J; Experimental Nephrology Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, 08907, Spain.; Fundació Bosch i Gimpera, University of Barcelona, Barcelona, 08028, Spain., Antón Pampols P; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain., Gomà M; Pathology Department, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, 08907, Spain., Fulladosa X; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain.; Faculty of Medicine, Bellvitge Campus, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, 08907, Spain., Cruzado JM; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain.; Faculty of Medicine, Bellvitge Campus, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, 08907, Spain., Torras J; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain.; Faculty of Medicine, Bellvitge Campus, University of Barcelona, L'Hospitalet de Llobregat, Barcelona, 08907, Spain., Draibe J; Nephrology Department, Bellvitge University Hospital. Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Feixa Llarga S/N, Barcelona, 08907, Spain.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 May 03; Vol. 22 (1), pp. 421. Date of Electronic Publication: 2024 May 03.
DOI: 10.1186/s12967-024-05177-9
Abstrakt: Introduction: Immune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2-5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients.
Methods: Twenty C57BL6J mice received 200 µg of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNFα, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression.
Results: Cisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity.
Conclusions: Only mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker.
(© 2024. The Author(s).)
Databáze: MEDLINE
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