Abstract: FR-PO189
Lung Cancer Induces Kidney Fibrosis and Primes the Kidney for Cisplatin-Induced Nephrotoxicity
Session Information
- Onconephrology: Clinical and Research Advances - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1600 Onconephrology
Authors
- Orwick, Andrew, University of Louisville, Louisville, Kentucky, United States
- Sears, Sophia Marie, University of Louisville, Louisville, Kentucky, United States
- Doll, Mark A., University of Louisville, Louisville, Kentucky, United States
- Shah, Parag P., University of Louisville, Louisville, Kentucky, United States
- Beverly, Levi J., University of Louisville, Louisville, Kentucky, United States
- Siskind, Leah J., University of Louisville, Louisville, Kentucky, United States
Background
Cisplatin is a common first-line treatment for many solid organ tumors. However, its effectiveness is restricted by dose-limiting nephrotoxicity. Thirty percent of cancer patients treated with cisplatin develop acute kidney injury (AKI), which requires a cessation in treatment. There are no treatment options to prevent or treat cisplatin-induced kidney injury. Historically the models used to study cisplatin-induced AKI involve a single high dose of cisplatin and do not include the co-morbidity of cancer. Our lab designed a low-dose repeated cisplatin model that results in the development of kidney fibrosis and chronic kidney disease (CKD). We hypothesized that including the comorbidity of lung cancer will potentiate the cisplatin-induced fibrosis and CKD.
Methods
Eight- to ten-week-old B6;129 mice were randomly assigned into four treatment groups: 1. non-cancer + vehicle, 2. non-cancer + cisplatin, 3. cancer + vehicle, 4. cancer + cisplatin. In the cancer groups, 10,000 lung adenocarcinoma cells were injected subcutaneously seven days prior to the start of cisplatin treatment. Cisplatin or saline was administered via intraperitoneal injection once a week for four weeks. Animals were euthanized 72 hours following their final cisplatin injection.
Results
Tumor-bearing vehicle control mice had elevated kidney injury markers, reduced markers of kidney function, and increased kidney fibrosis compared to non-tumor vehicle-treated mice. Cisplatin-induced kidney fibrosis was significantly worsened in tumor-bearing mice compared to mice without tumors.
Conclusion
The presence of lung tumors is sufficient to alter kidney biology, induce fibrosis, and reduce renal function, independent of cisplatin treatment, and importantly sensitized the kidneys to cisplatin-induced nephrotoxicity. Understanding the tumor-kidney crosstalk may provide mechanistic insights and uncover novel therapeutic targets for preventing and treating cisplatin-induced AKI and CKD.
Funding
- NIDDK Support