Donor Nutritional Status-a Determinant of Liver Preservation Injury1

Abstract

In liver transplantation, the quality of the liver is determined by a number of factors including donor nutritional status. Livers from fasted donors appear to tolerate long-term preservation better than livers from fed donors. In this study we repeated earlier results and obtained 31% (4/13) survival after 40-hr preservation of livers from fed donor Brown Norway rats and 67% (8/12) survivors with donor livers from 4-day-fasted rats (P = 0.154). The explanation for this improvement is not known but may be due to inactivation of Kupffer cells due to nutritional depletion of the liver. Kupffer cell activation has been one explanation advanced to explain how cold storage injuries livers during reperfusion (transplantation). In this study, we have measured how donor fasting affects Kupffer cell function (phagocytosis of colloidal carbon) after preservation of the rat liver. In addition, we measured how enhancing liver glycogen by feeding glucose to the rat donors affected outcome and liver functions tested by isolated perfusion after 24- and 40-hr cold storage of the liver. Preservation did not cause inactivation or activation of Kupffer cell phagocytosis of colloidal carbon. In livers with 0-hr preservation, colloidal carbon uptake was 3.1 +/- 0.2 mg/g/hr, after 40-hr preservation uptake was 3.8 mg/g/hr (P < 0.05 vs. 0 hr) (fed) and 2.7 +/- 0.3 mg/g/hr (fasted, P, 0.05 vs. 0-hr and 40-hr-fed). Thus, the improved survival obtained with livers from fasted donors does not appear related to inactivation of Kupffer cell phagocytosis. Although livers from fasted donors showed improved survival, there was extensive hepatocellular injury as indicated by large LDH release from the livers after 40-hr cold storage as tested by isolated perfusion. LDH released into the perfusate increased from 35.8 +/- 10.1 U/L (fed, 40-hr CS) to 301 +/- 65 U/L (fasted, 40-hr CS) after 1-hr reperfusion. AST release showed a similar pattern and bile production was suppressed more in livers from fasted donors than fed donors. Feeding rats glucose elevated liver glycogen and significantly reduced hepatocellular injury as measured by LDH release and AST release in the isolated perfused liver after 40-hr cold storage. Feeding rats glucose (40% in drinking water for 4 days) also improved survival: fed+glucose = 85% survival versus 31% survival with no glucose and fasted+glucose = 92% survival versus 67% survival with no glucose. These results show that both extensive donor fasting and glucose feeding enhanced outcome in orthotopic liver transplantation. This dilemma (both fasting and feeding improved survival) are discussed in terms of how the interactions between Kupffer cells and hepatocytes affect liver viability. Donor fasting is probably impractical clinically as a method to improve the donor liver, but elevating liver glycogen by glucose supplementation is possible and may lead to improved preservation and outcome in liver transplantation.

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

“…For ground squirrels, the gall bladder was ligated and removed. The portal vein was cannulated, and the livers were flushed with 15 ml 4°C UW solution, removed, and either used immediately (0 h preservation "control") or cold stored in UW solution for 24 -96 h (27,28).…”

“…Perfusate samples were collected every 30 min for blood gas analyses and release of lactate dehydrogenase (LDH). The LDH concentration was measured spectrophotometrically using a commercial kit (340-LD; Sigma, St Louis, MO) and expressed per gram wet liver mass (U ⅐ l Ϫ1 ⅐ g) (27,28). Bile was collected at 30-min increments, weighed, and expressed per gram wet liver mass (mg/g).…”

“…Uptake of colloidal carbon (CC) was used as a measure of Kupffer cell phagocytosis. CC (black India ink, Pelikan 17) was prepared as described previously (27). The density of CC was analyzed by overnight desiccation (mg/ml).…”

“…During this time, perfusate samples were collected every 5 min to determine uptake of CC by comparing the absorbance at 623 nm of the perfusate going into the liver to the perfusate leaving the liver. The rate of CC uptake was expressed as micrograms per minute times grams liver tissue (11,27).…”

Untitled

“…25,[63][64][65][66][67] Glycogen may help maintain tissue stores of high-energy adenylates over the course of preservation. 25 Glycogen is consumed considerably during ischemic rewarming of the graft, 25,67 as well as during the early period of reperfusion.…”