Abstracts
1997 Digestive Disease Week

The relationship between TNF kinetics and allograft injury following prolonged preservation-reperfusion in rat livers.

HN Sankary, D Yin, P Foster, J Williams. Department of Surgery, Rush-Presbyterian St Lukes Medical Center. Chicago, IL.

Impaired allograft function in livers subjected to prolonged storage is associated with and possibly results from injury caused by increased circulating levels of TNF. We have previously presented data implicating increased TNF concen-trations as causative of allograft injury. Using two novel experimental models, one with a liver transplanted and splanchnic viscera removed(asplanchnic), and another with the portal vein cross clamped(anhepatic), we have established that the intestine may release a significant quantity of TNF following revascularization. Allograft injury may therefore reflect altered hepatic uptake of intestinal derived TNF. The purpose of this study was to determine the effect of increasing periods of cold ischemia on hepatic uptake of circulating TNF. Male Lewis rats underwent orthotopic liver transplants (OLT) using livers stored for either short (2hr) or long(16hr) time intervals. Following implantation rats were administered a single intravenous dose 10µg/kg of human recombinant TNF. TNF levels from the inferior vena-cava (IVC), portal vein(PV), and hepatic veins(HV)were serially determined using a ELISA assay specific for human TNF which was shown to have negligible cross reactivity for rat TNF. In this model one could determine changes in hepatic uptake of TNF without interference from TNF of autogenous origin. [Figure not available.] RESULTS:

AUC IVC(pg/ml*min)       AUC PV           AUC HV
  2 hr        18404±2894               17718±1748       13626±1080
  16 hr       38844±3131*              36816±2954*      36720±3760*
* P<.001 compared with 2 hr (t-test)

CONCLUSIONS: 1) Examining pharmacokinetics of human recombinant TNF following an intravenous bolus in a rat OLT model allowed us to separate uptake from production. 2) Although levels in the IVC were slightly higher, TNF rapidly equilibrated into all compartments. 3) The significant increase in AUC of the time-concentration curve when preservation times were prolonged suggests that increasing cold ischemic time decreases hepatic clearance of TNF. 4) These findings support our previous contention that increased levels of TNF following revascularization of livers subjected to prolonged periods of CIT are not necessarily related to increased hepatic production, but instead may reflect decreased elimination.