Abstract: SA-PO583
Renal Hypercoagulability Is Front and Center in Ischemic Injury
Session Information
- AKI: Other Mechanisms and Cell Cultures
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Dominguez, Jesus H., VAMC, Indianapolis, Indiana, United States
- Dominguez, James M., Indiana University, Indianapolis, Indiana, United States
- Xie, Danhui, IUPUI, Indianapolis, Indiana, United States
- Kelly, Katherine J., Indiana University, Indianapolis, Indiana, United States
Background
The transition of acute kidney injury (AKI) to chronic kidney disease (CKD) is common and misunderstood. We hypothesize that widespread renal clotting impairs reperfusion following renal ischemia in rats. This renal response is manifested as no-reflow in the microcirculation, causing swaths of renal micro ischemia, inflammation, apoptosis and fibrosis.
Methods
SD rats (n = 5/group) were subjected to 50 minutes of renal ischemia and then to 6 days of reperfusion. We used RNAseq comprehensive transcriptome analysis and measured 12,159 renal transcripts in sham and ischemic rats. The data were analyzed with established informatics tools.
Results
Renal ischemia activated the intrinsic renal clotting system and clotted renal microvessels. This response to injury included prothrombotic stimulation manifested by renal tubular activation of tissue factor (up 1.9 fold; p<0.002), and inhibition of tissue factor pathway inhibitor (down 1.44 fold, p = 0.008). Moreover, all three chains of renal fibrinogen were upregulated (up to 33 fold; 2.2E-10) and circulating fibrinogen also surged: 140±30 to 719±29 mg/dl, p<0.0024. Renal plasminogen was not expressed. There was major inhibition of fibrinolysis represented by activation of plasminogen activator inhibitor (up 5.6 fold; p = 1.7E-7), lack of response in renal urokinase and tisue plasminogen activator, and inhibition of plasminogen activator kallikrein (down 10 fold, p = 1.85E-6). In addition the thrombin receptor F2rl1 was activated 2 fold (p<0.0001). Complement component C1qa,b,c increased 3 fold (p <0.0001), C3 (up 5 fold p= 1.2E-5), and C4 a,b (up 12.56 and 20 fold respectively, p = 1.9E-13). These renal mRNA changes were associated with similar responses in renal cognate proteins and fibrin deposition. Kegg pathway analysis confirmed differential expression in ischemia of coagulation and complement pathways P=2.68 x 10-3.
Conclusion
We suggest the renal pro-thrombotic and fibrinolytic balance is essential to protect and assure competent blood flow. In renal injury, this balance is disrupted in favor of hypercoagulability. The risk to renal microthrombosis is further enhanced by complement activation and inhibition of a robust renal fibrinolytic system. We propose that in ischemic AKI the most optimal option is to re-activate fibrinolysis, anticipating that anti-coagulant agents are unlikely to be effective.
Funding
- Veterans Affairs Support