Cisplatin, a chemotherapeutic used for the treatment of solid cancers, has nephrotoxic side effects leading to acute kidney injury (AKI). Cisplatin cannot be given to patients that have comorbidities that predispose them to an increased risk for AKI. Even without these comorbidities, 30% of patients administered cisplatin will develop kidney injury, requiring the oncologist to withhold or reduce the next dose, leading to a less effective therapeutic regimen. Although recovery can occur after one episode of cisplatin-induced AKI, longitudinal studies have indicated that multiple episodes of AKI lead to the development of chronic kidney disease, an irreversible disease with no current treatment. The standard mouse model of cisplatin-induced AKI consists of one high dose of cisplatin (>20 mg/kg) that is lethal to the animal 3 days later. This model does not accurately reflect the dosing regimen patients receive nor does it allow for the long-term study of kidney function and biology. We have developed a repeated dosing model whereby cisplatin is given once a week for 4 wk. Comparison of the repeated dosing model with the standard dosing model demonstrated that inflammatory cytokines and chemokines were induced in the repeated dosing model, but levels of cell death were lower in the repeated dosing model. The repeated dosing model had increased levels of fibrotic markers (fibronectin, transforming growth factor-β, and α-smooth muscle actin) and interstitial fibrosis. These data indicate that the repeated dosing model can be used to study the AKI to chronic kidney disease progression as well as the mechanisms of this progression.

Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury.

Cisplatin is used to treat many solid cancers, but its dose-limiting side effect is nephrotoxicity, causing acute kidney injury in 30% of patients. Previously, we have developed a mouse model that better recapitulates the cisplatin dosing regimen humans receive and found that repeated dosing of cisplatin induces interstitial renal fibrosis. Chronic kidney disease is progressive and is characterized by chronic inflammation, worsening interstitial fibrosis, development of glomerulosclerosis, and endothelial dysfunction. To determine if damage caused by repeated cisplatin dosing results in bona fide chronic kidney disease, mice were treated with our repeated dosing regimen and then aged for 6 mo. These mice had progressive, chronic inflammation and worsened interstitial fibrosis compared with mice euthanized after day 24. Mice aged for 6 mo developed glomerular pathologies, and endothelial dysfunction was persistent. Mice treated with only two doses of cisplatin had little inflammation or kidney damage. Thus repeated dosing of cisplatin causes long-term effects that are characteristic of chronic kidney disease. This translational mouse model of cisplatin injury may better represent the 70% of patients that do not develop clinical acute kidney injury and can be used to identify both biomarkers for early injury, as well as novel therapeutic targets for the prevention of cisplatin-induced chronic kidney disease.

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C57BL/6 mice are one of the most commonly used mouse strains in research, especially in kidney injury studies. However, C57BL/6 mice are resistant to chronic kidney disease-associated pathologies, particularly the development of glomerulosclerosis and interstitial fibrosis. Our lab and others developed a more clinically relevant dosing regimen of cisplatin (7 mg/kg cisplatin once a week for four weeks, mice euthanized at Day 24) that leads to the development of progressive kidney fibrosis in FVB/n mice. However, we found that treating C57BL/6 mice with this same dosing regimen does not result in kidney fibrosis. In this study, we demonstrate that increasing the dose of cisplatin to 9 mg/kg once a week for four weeks is sufficient to consistently induce fibrosis in C57BL/6 mice while maintaining animal survival. In addition, we present that cohorts of C57BL/6 mice purchased from Jackson one year apart and mice bred in house display variability in renal outcomes following repeated low dose cisplatin treatment. In depth analyses of this intra-animal variability revealed CCL2 as a marker of cisplatin-induced kidney injury through correlation studies. In addition, significant immune cell infiltration was observed in the kidney after four doses of 9 mg/kg cisplatin, contrary to what has been previously reported. These results indicate that multiple strains of mice can be used with our repeated low dose cisplatin model with dose optimization. Results also indicate that littermate control mice should be used with this model to account for population variability.