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Abstract: SA-PO237

Diversity Outbred Mouse Model for Investigating Genetic Determinants of Cisplatin Nephrotoxicity

Session Information

Category: Onconephrology

  • 1700 Onconephrology


  • Wang, Yves T., University of Rochester Medical Center, Rochester, New York, United States
  • Le, Thu H., University of Rochester Medical Center, Rochester, New York, United States

Cisplatin is a commonly used chemotherapy agent that is highly effective against several cancers. However, it has significant toxicity to several organs including the kidney. This has a significant impact on patient outcomes, as 50% of patients have to reduce dosages or discontinue use of cisplatin and up to 30% suffer from acute kidney injury (AKI). The causes of inter-individual variability in cisplatin nephrotoxicity are unknown, but evidence points to the involvement of genetic factors. We propose to use a mouse model with high genetic variability to identify potential gene candidates involved with modifying cisplatin nephrotoxicity. Here, we demonstrate the feasibility of using the Diversity Outbred mouse model, which was designed to mimic genetic heterogeneity in humans, in a small pilot study that demonstrates highly variable nephrotoxic response to chronic cisplatin administration.


Male and female Diversity Outbred mice (The Jackson Laboratory) were exposed to 9 mg/kg cisplatin subcutaneously weekly over 4 weeks (n = 8/sex) or to vehicle control (n = 4/sex). Three days after the last dose, plasma was collected and creatinine was measured by mass spectrometry and BUN was measured by a colorimetric assay at the UAB/SD O’Brien Center for Acute Kidney Injury Research.


Control mice had plasma creatinine levels of 0.06±0.02 mg/dL [range: 0.04-0.08] in males and 0.07±0.02 mg/dL [0.06-0.11] in females. Compared to controls, cisplatin treated mice had significantly elevated plasma creatinine levels of 0.21±0.10 mg/dL [0.08-0.37] in males (p=0.0051) and 0.28±0.19 mg/dL [0.11-0.70] in females (p=0.016). Similarly, BUN was elevated in treated males (77.3±26.4 mg/dL [21.3-104.1] vs 26.5±8.4 mg/dL [18.1-36.5], p=0.00073) and females (65.7±27.5 mg/dL [21.9-92.0] vs 23.5±7.6 mg/dL [12.4-29.6], p=0.0030).


The Diversity Outbred mice display highly variable degrees of AKI after cisplatin exposure. While the majority of treated mice exhibited significantly elevated markers of AKI, some had markers similar to control mice. This model is suitable for quantitative trait loci (QTL) mapping to identify genes that modify susceptibility to cisplatin nephrotoxicity. Identification of these genes may enable pharmacogenetic application to tailor chemotherapy and enable development of adjunct therapies to limit cisplatin-induced AKI.