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A Model of Chronic Cisplatin-Induced Kidney Injury in Mice with Cancer

Background: Patients with cancer may require chronic administration of cisplatin (Cis). However, most previous in vivo studies of Cis- induced AKI (CIA) have been in models of acute (3 days), high dose (25mg/kg) Cis administration in normal mice. Aim of study was to develop a model of 4 week, low dose (5 mg/kg) Cis administration in mice with cancer, that resembles the Cis dosing regimen for 4 cycles that is used in humans with cancer. Methods: Mice were injected with 105 lung cancer cells into the flank at day 0. The first dose of Cis 5 mg/kg or vehicle (Veh) was given at day 9. Cis 5 mg/kg or Veh was then given on days 16, 20, 23 and 27 for a total of 5 doses. Mice were sacrificed on day 29. Tumors were measured on day 16, 20 and 29. IL-33 and CXCL1 (IL-8) are pro- inflammatory cytokines. IL-33 signals via the ST2 receptor on CD4 T cells. We have previously described the role of the IL-33/ST2/CD4 T cell/CXCL1 axis in a 3 day model of CIA. Results: AKI model: BUN (mg/dL) was 23 in Veh and 114 in Cis (P<0.001). SCr (mg/dL) was 0.2 in Veh and 0.5 in Cis (P<0.001). ATN score was 0 in Veh and 3.5 in Cis (P<0.001). Apoptosis in tubular cells (/HPF) was 0 in Veh and 1.2 in Cis (P<0.001). Cancer model: Tumor volume (mm3) in Veh was 308 on day 16 and 1791 on day 29 (P<0.001). Tumor volume in Cis was 604 on day 16 and 702 on day 29 (NS). At the end of the study, tumor weight (g) was 1.23 in Veh and 0.46 in Cis (P<0.001). IL-33/ST2/CD4 T cell/CXCL1 signaling: IL-33 (pg/mg) was 70 in Veh and 198 in Cis (P<0.001). CXCL1 (pg/mg) was 1.9 in Veh and 58 in Cis (P<0.001). CD4 T cell subset (% of live cells) on flow cytometry was 13 in Veh and 35 in Cis (P<0.001). In time course experiments, the increase in IL-33, CD4 T cells and CXCL1 at week 1 preceded the increase in BUN and SCr at week 2 after Cis administration. Conclusions: We have developed a model of chronic Cis- administration that resembles the human condition in mice with cancer. There are increases in BUN, SCr, ATN, apoptosis, IL-33, CD4 T cells and CXCL1 and also a significant chemotherapeutic effect of Cis on the tumor. The effect of IL-33, ST2 or CXCL1 inhibition on the CIA and the chemotherapeutic effect of Cis will be interesting in future experiments.

Chronic Cisplatin-Induced Kidney Injury; Mice

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