Cytokines monitored by microdialysis detect rejection earlier than current methods in liver transplantation

Introduction

The outcome of liver transplantation is steadily improving. There is still need for earlier detection of complications such as hepatic artery thrombosis and rejection. In an earlier in vitro study we showed that the CMA microdialysis system with a 100 kDa pore size membrane can be used to measure the selected cytokines and complement. We monitored patients undergoing liver transplantation with microdialysis continuously for a week postoperatively, and analyzed both parameters to detect ischemia, and cytokines and anaphylatoxins to explore whether rejection was detected earlier than with the standard methods.

Methods

Twenty patients undergoing 22 liver transplantations were included. Two microdialysis catheter were introduced in the liver and one in subcutaneous tissue. We analyzed metabolic parameters (glucose, pyruvate, glycerol and lactate), and IL-6, IL-8, MCP-1, IP-10, and C5a.

Results

Fourteen patients had an uneventful course postoperatively, judged clinically and by routine biochemical markers and ultrasound Doppler. These patients had a median lactate starting at 3.5 mM (2 hours after reperfusion) falling to below 2 mM during the first 24 hours, and thereafter staying low. The L/P ratio (a specific measure of ischemia) dropped from about 20 to below 10. These patients had a steady rise in IP-10 from 200 to 3,000 pg/ml, and also a slight raise in IL-6 initially. Case 1. The male patient had a steadily increasing L/P ratio during the 7 days of microdialysis measurements, indicating an insufficient blood supply. He underwent surgery 5 days later and a hepatic artery thrombosis was found. A biopsy was done during the operation showing an acute rejection. There was a significant rise in IP-10 to 13,000 pg/ml 7 days before the diagnosis of rejection. Case 2. The female patient had an acute rejection verified by biopsies on day 10 postoperatively. Her IL-8, IP-10 and C5a increased 10-fold to 100-fold in the liver 3 days earlier than an increase in liver enzymes and 5 days before the rejection was verified by biopsy.

Conclusion

We have described the normal course of the four cytokines IL-6, IL-8, MCP-1 and IP-10 and complement C5a after liver transplantation, as well as metabolic parameters to detect ischemia. In two patients with rejection we found a large increase in IP-10, IL-8 and complement split-product C5a in the liver but not in the subcutis 3–5 days before any other parameter of liver injury.