Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin

Nephrotoxicity is a major complication of cisplatin-based chemotherapy, leading to acute kidney injury in ca. 30% of patients, with no preventive intervention or treatment available for clinical use. Cilastatin has proved to exert a nephroprotective effect for cisplatin therapies in in vitro and in vivo models, having recently entered clinical trials. A deeper understanding at the molecular level of cisplatin-induced renal damage and the effect of potential protective agents could be key to develop successful nephroprotective therapies and to establish new biomarkers of renal damage and nephroprotection. A targeted lipidomics approach, using LC-MS/MS, was employed for the quantification of 108 lipid species (comprising phospholipids, sphingolipids, and free and esterified cholesterol) in kidney cortex and medulla extracts from rats treated with cisplatin and/or cilastatin. Up to 56 and 63 lipid species were found to be altered in the cortex and medulla, respectively, after cisplatin treatment. Co-treatment with cilastatin attenuated many of these lipid changes, either totally or partially with respect to control levels. Multivariate analysis revealed that lipid species can be used to discriminate renal damage and nephroprotection, with cholesterol esters being the most discriminating species, along with sulfatides and phospholipids. Potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were also found.

Automated summary

Nephrotoxicity is a common complication of cisplatin-based chemotherapy, but there is currently no preventive intervention or treatment available for clinical use. Cilastatin has shown to have a nephroprotective effect in in vitro and in vivo models and is now in clinical trials. Understanding the molecular mechanisms of cisplatin-induced renal damage and the effects of potential protective agents could lead to successful nephroprotective therapies and new biomarkers of renal damage and protection. A targeted lipidomics approach was used to quantify lipid species in kidney extracts from rats treated with cisplatin and/or cilastatin, showing significant changes in lipid levels after cisplatin treatment which were attenuated by co-treatment with cilastatin. Cholesterol esters, along with sulfatides and phospholipids, were found to be the most discriminating lipid species in differentiating renal damage from nephroprotection. Additionally, potential diagnostic biomarkers of cisplatin-induced renal damage and cilastatin nephroprotection were identified.