Abstract: FR-PO114
Renal Ischemia-Reperfusion Followed by Sepsis Increases Mortality Despite Reducing Multiorgan Damage: Reversal by IL-6
Session Information
- AKI: Mechanisms - Inflammation/Sepsis/Remote Injury
November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Tsuji, Takayuki, NIDDK/NIH, Bethesda, Maryland, United States
- Kim, Myung-Gyu, Korea University Anam Hospital, Seoul, Korea (the Republic of)
- Street, Jonathan, NIDDK/NIH, Bethesda, Maryland, United States
- Zhou, Hua, The Affiliated Shengjing Hospital of China Medical School, Shenyang/China, LIAONING, China
- Leelahavanichkul, Asada, Chulalongkorn University, Bangkok, Thailand
- Hu, Xuzhen, NIDDK/NIH, Bethesda, Maryland, United States
- Yuen, Peter S.T., NIDDK/NIH, Bethesda, Maryland, United States
- Star, Robert A., NIDDK/NIH, Bethesda, Maryland, United States
Background
Sepsis frequently develops after AKI and portends a poor prognosis. We previously showed that sepsis 48 hours after ischemia reperfusion (I/R) AKI worsened kidney function and survival compared to sepsis alone, although there was less liver, muscle, spleen damage, and systemic cytokines. Thus, AKI unexpectedly dissociated renal function from systemic responses to sepsis. We hypothesized that the I/R injured kidney could alter the systemic response to subsequent sepsis. We investigated pathophysiological conditions of sepsis after AKI focusing on IL-6 and its upstream mediator Tumor necrosis factor-inducible gene 6 (TSG-6) which has anti-inflammatory properties.
Methods
We used 12 weeks old male C57/BL6 mice. We performed 40 minutes bilateral I/R for AKI, waited 48 hours, then performed cecal ligation and puncture (CLP) for sepsis. We measured outcomes at 48 hours after I/R and 24 hours after CLP. We also performed a 4 day survival study. In some animals, bilateral nephrectomy was performed at the same time of CLP surgery.
Results
I/R intensified sepsis-induced AKI [sCr; I/R+CLP vs shamI/R+CLP, 1.40±0.58 vs 0.82±0.37 mg/dl (p<0.05)]. Survival rate in I/R+CLP was significantly worse than shamI/R+CLP. In contrast, AST, LDH and CK, systemic inflammatory cytokines (HMGB-1, IL-10 and IL-6) and spleen apoptosis (immunohistochemistry of active caspase 3) were significantly lower in I/R+CLP than shamI/R+CLP. Although I/R caused a slight elevation of systemic IL-6 at 48 hours, prior I/R surgery suppressed subsequent CLP stimulated IL-6, that was reversed by bilateral nephrectomy. Surprisingly, continuous administration of IL-6 starting immediately before CLP surgery improved the mortality of sepsis after I/R. In contrast, it worsened mortality in sepsis alone. Systemic and kidney TSG-6 was significantly increased at 48 hours after I/R injury and 24 hours after CLP in I/R+CLP compared to CLP alone.
Conclusion
AKI, followed by sepsis, worsened survival and kidney function, although liver and muscle enzymes, systemic cytokines and spleen apoptosis were improved compared with sepsis alone. Treatment with IL-6 improved survival of sepsis after AKI, counterintuitively. TSG6 derived from I/R injured kidney might contribute to changes in systemic and organ responses to subsequent sepsis.
Funding
- NIDDK Support