Abstract: PO2172
Acute Myeloid Leukemia Worsens Sepsis-Induced AKI
Session Information
- Onco-Nephrology - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Onco-Nephrology
- 1500 Onco-Nephrology
Authors
- Tsuji, Takayuki, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Tsuji, Naoko, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Yamashita, Tetsushi, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Hu, Xuzhen, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Yuen, Peter S.T., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Star, Robert A., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Group or Team Name
- Renal Diagnostics and Therapeutics Unit
Background
Patients with hematological malignancies are at high risk for acute kidney injury (AKI), which is associated with high morbidity and mortality. Sepsis is the main cause of AKI in ICU patients with hematologic malignancies. However, the contributions that host or cancer cells make to systemic inflammation during sepsis-induced AKI is not known.
Methods
We created a mouse xenograft model of acute myelogenous leukemia (AML) associated sepsis AKI. Human leukemia HL-60 cells were injected into the tail vein of 6 week-old male NOD/SCID/IL-2Rγnull(NSG) mice. After engraftment 2 weeks later, cecal ligation and puncture (CLP) was performed to induce sepsis (n=8-12 per group). Tumor engraftment in the bone marrow (BM) and blood tumor burden were measured by flow cytometry of human CD33 and human CD45 double positive cells. Multiple organ damage, and both mouse and human systemic cytokines were evaluated at 24 h after CLP or sham surgery.
Results
AML intensified sepsis-induced AKI. Both BUN and LDH were significantly higher in AML+CLP than CLP alone (AML+CLP vs vehicle+CLP, BUN 74.5±25.4 vs 42.7±25.3 mg/dl, LDH 3,969±1,720 vs 1,863±661 mg/dl, p<0.05). CLP dramatically increased the percentage of circulating leukemia cells (pre CLP vs post CLP, 2.2±1.3 % vs 20.6±13.3 %, p<0.05). Tumor burden in either BM or blood did not correlate with AKI severity. Systemic mouse IL-6 in AML+CLP at 24 hours after CLP was significantly higher than CLP alone (45.9±2.4 vs 15.1±2.4 ng/mL, p<0.05). Systemic human IL-6 in AML+CLP was higher, but not significantly, than vehicle+CLP. There was no correlation between human cytokines and severity of AKI, although human cytokines (IL-6 and TNFα) significantly correlated with tumor burden in both BM and blood at 24 hours after CLP.
Conclusion
We established a clinically relevant mouse xenograft model of human leukemia associated sepsis AKI. Leukemia intensified sepsis-induced AKI, and sepsis AKI increased the numbers of circulating AML cells. Systemic cytokines derived from the human leukemia cells correlated with tumor burden, but not with the severity of sepsis-induced AKI. Whereas malignant cells do not produce circulating cytokines that directly drive the systemic immune response to subsequent sepsis-induced AKI, cell-cell interactions in the BM niche may impact systemic inflammation indirectly, possibly through mouse IL-6.
Funding
- NIDDK Support