Changes in liver graft rejections over time.

Incidence and possible risk factors of acute rejection, time to acute rejection, graft rejection within 3 months, multiple rejections within 1 year, steroid-resistant rejection, and graft lost to chronic rejection or to chronic dysfunction were evaluated in 388 liver transplantations. HLA matches, anti-HLA class I antibodies, positive crossmatch test, or positive cytomegalovirus serology did not have an effect on the occurrence of acute or chronic rejection. Increased total bleeding diminished occurrence of acute rejection, lengthened the time to acute rejection, and reduced the risk of steroid-resistant rejection. Immunological pretransplant factors did not have a major effect on the occurrence of rejection after liver transplantation. Different types of rejections diminished over time and the time period to the first acute rejection increased, although the basic immunosuppression stayed mainly the same over 20 years in our center.

Risk factors predicting survival of liver transplantation.

Prognostic models were developed for analyzing graft survival in a single-center study consisting of all 388 adult liver transplantations performed during 20 years. Proportional hazard models and generalized linear models were used to assess which risk factors, related to donor and recipient characteristics as well as graft preservation and operation, had an effect on graft survival. The prognostic modeling evidenced favorable trends in graft survival time during the successive quinquennials 1982-1987, 1988-1992, and 1993-1997, in comparison to the referent time period 1998-2002. Significant predictors of graft survival time were donor's age, recipient-donor gender compatibility, recipient's blood group, intraoperative blood transfusion, size of the transplanted organ, and indication for transplantation. Conventional histocompatibility matching did not correlate with graft outcome.

Cytomegalovirus infection, viral DNA, and immediate early-1 gene expression in rejecting rat liver allografts.

BACKGROUND: Cytomegalovirus (CMV) infection has been linked to acute and chronic rejection. We have previously shown that concomitant rat cytomegalovirus (RCMV) infection increases portal inflammation and bile duct destruction in rejecting rat liver allografts. Many of the pro-inflammatory effects of CMV have been attributed to the immediate early (IE) proteins of CMV. We wanted to investigate whether RCMV and IE-1 gene expression persist in the liver graft in our model. METHODS: Liver transplantations were performed from PVG (RT1c) into BN (RT1n) rats. One day after transplantation, the rats were infected with RCMV. No immunosuppression was given. The graft infection was studied by viral culture, immunofluorescence, DNA in situ hybridization and RT-PCR for the detection of IE-1 mRNA at various time points. RESULTS: RCMV caused an active infection from 5 days to 2 weeks after transplantation, during which infectious virus was found in the graft. Thereafter the cultures were negative. RCMV antigens and DNA were found in hepatocytes, endothelial, inflammatory, and bile duct cells during the active infection. At 4 weeks, RCMV DNA positive hepatocytes, endothelial, inflamma tory, and bile duct cells could still be found, but in much smaller quantities. IE-1 mRNA expression was, however, only detected during the active infection, not at 4 weeks postinfection. CONCLUSIONS: RCMV IE-1 expression does not persist in the graft after the active infection, although some viral DNA can be detected in the graft up to 4 weeks. In our model, the CMV-induced increase in graft damage does not seem to require the continued expression of IE-1.

Long-term results of 1047 cadaveric kidney transplantations with special emphasis on initial graft function and rejection.

We studied the effect of initial graft function and acute rejection on graft survival in 1047 cadaveric renal transplantations during 1991-1997 with a constant policy of donor selection, graft allocation, and immunosuppression. The overall 1- and 5-year patient survival rates were 96 % and 88 %, and the 1- and 5-year graft survival (GS) rates were 92 % and 78 %. Delayed graft function (DGF) occurred in 31 % and there were 1.2 % never-functioning grafts. One-year GS in transplantations with early graft function (EGF) was 95 % compared to 87 % in DGF (P < 0.001). Donor age and cause of death, type of graft perfusion and cold ischemia time, and type and length of dialysis treatment were significant factors in determining the onset of graft function. These factors did not have a significant direct effect on GS. Early ( < 100 days) acute rejection occurred in 25 %. In transplantations without rejection, the 1 and 5-year GS was 93.3 % and 80.8 %. In acute rejection responding to steroids, the GS was equal to that up to 3 years, but after that a significantly worse survival rate was observed (1- and 5-year GS: 93.6 % and 73.4 %). DGF was detrimental to GS both in transplantations without rejection and in all rejection types.

Colorectal dysplasia and carcinoma in patients with ulcerative colitis and primary sclerosing cholangitis.

BACKGROUND: The aim of this study was to evaluate the role of primary sclerosing cholangitis (PSC) as a cofactor in the dysplasia-carcinoma sequence in ulcerative colitis (UC). METHODS: Forty-five patients with UC and concomitant PSC and 45 pair-matched control patients with UC only were examined for colorectal dysplasia and carcinoma. RESULTS: The median duration of UC was 11 years in the group with UC and PSC and 15 years in the control group. Thirteen of the 45 patients (29%) with UC and PSC had colorectal neoplasia: 4, carcinoma; 2, high-grade dysplasia; and 7, low-grade dysplasia. Four of the 45 control patients (9%) had neoplastic findings: 1, carcinoma; 1, high-grade dysplasia, and 2, low-grade dysplasia (P < 0.05). CONCLUSION: The results suggest that the risk of colorectal dysplasia and carcinoma in patients with UC is increased by concomitant PSC.

Serum aminoterminal propeptide of type III procollagen (S-PIIINP) and hepatobiliary dysfunction in patients with ulcerative colitis.

The aim of the study was to estimate the usefulness of measuring the circulating concentration of serum aminoterminal propeptide of type III collagen (S-PIIINP) in screening for hepatobiliary diseases in patients with ulcerative colitis. S-PIIINP was measured in 69 patients with ulcerative colitis and normal liver biochemistry, in 14 patients with ulcerative colitis and elevated catalytic concentration of alkaline phosphatases in serum (S-ALP, EC 3.1.3.1) but without primary sclerosing cholangitis (PSC), and in 20 patients with ulcerative colitis and PSC. The median S-PIIINP was 3.1 micrograms l-1 in patients with ulcerative colitis and normal liver biochemistry, 4.3 micrograms l-1 in patients with ulcerative colitis and hepatobiliary disorder other than PSC and 8.9 micrograms l-1 in those with ulcerative colitis and PSC. When the S-PIIINP cut-off level was set at 5.0 micrograms l-1, 1% of the patients with ulcerative colitis and normal liver biochemistry, 21% of those with hepatobiliary disorder, not PSC, and 90% of the patients with PSC had S-PIIINP values above that concentration. In conclusion, S-PIIINP above 5.0 micrograms l-1 in a patient with ulcerative colitis strongly suggests concomitant PSC.

Failure of dobutamine to improve liver oxygenation during resuscitation with a crystalloid solution after experimental haemorrhagic shock.

OBJECTIVE: To evaluate the effects of dobutamine on peripheral and hepatic tissue oxygen tensions during the treatment of haemorrhagic shock. DESIGN: Randomised, controlled trial. SETTING: University hospital, Finland. SUBJECTS: 12 Piglets, weight 20 kg. INTERVENTIONS: Haemorrhagic shock (40% of blood volume removed) and resuscitation with crystalloid solution. Dobutamine infused (6.5 micrograms/kg/min) during resuscitation in 6 animals and 6 served as controls. MAIN OUTCOME MEASURES: Haemodynamic and systemic oxygen transport variables. Hepatic, subcutaneous, transcutaneous, and conjunctival oxygen tensions measured continuously with polarographic electrodes. RESULTS: All values decreased significantly during bleeding. Resuscitation restored the mean arterial pressure in both groups, and cardiac output exceeded the baseline by 24% in the dobutamine group (p < 0.05 compared with control). There was no difference in oxygen delivery and consequently tissue oxygen tensions remained at the control level in the dobutamine group. CONCLUSIONS: Dobutamine infusion did not improve tissue oxygenation when used in addition to crystalloids to treat hypovolaemic shock.

Spontaneous recovery of post partus liver necrosis in a patient listed for transplantation.

The patient was a young previously healthy woman, who after a normal grosses, during delivery got severe abdominal pain. The liver function tests were highly pathological and the patient became anuric and developed first grade of encephalopathy. In computer tomography, 90% of the liver parenchyma was damaged and liver biopsy showed necrosis. The patient had fulminant hepatic failure including hepatorenal syndrome and was put on the Scandiatransplant high urgent waiting list for a liver transplant. No suitable liver was found. After eight days, the general situation of the patient was better and the liver function tests started to improve. She was taken off the waiting list. Twenty-seven days after delivery the patient was discharged in good condition. At check up six months later the patient was feeling well and the clinical tests were normal.

HLA antigens in ulcerative colitis and primary sclerosing cholangitis.

The aims of this study were to find out whether the alleles of the HLA class I or II region are associated with susceptibility to ulcerative colitis, and to show whether there is a difference or similarity in HLA associations between primary sclerosing cholangitis and ulcerative colitis. HLA-A, B, C and DR antigens were studied using the standard lymphocyte microcytotoxicity test in 24 Finnish patients with primary sclerosing cholangitis, 77 patients with ulcerative colitis, and 106 controls. HLA-B8 (54%) and DR3 (60%) were associated with primary sclerosing cholangitis. HLA-DR1 (46%) and DR6 (20%) seemed more common in ulcerative colitis than in controls. A positive association with Cw7 was common to both ulcerative colitis (25%) and primary sclerosing cholangitis (33%). Our results indicate that ulcerative colitis is more heterogeneous than primary sclerosing cholangitis in its HLA-DR associations.

Soybean phytoestrogen intake and cancer risk.

Because many Western diseases are hormone-dependent cancers, we have postulated that the Western diet, compared with a vegetarian or semi-vegetarian diet, may alter hormone production, metabolism or action at the cellular level. Recently, our interest has been focused on the cancer-protective role of some hormone-like diphenolic phytoestrogens of dietary origin, the lignans and isoflavonoids. The precursors of the biologically active compounds originate in soybean products (mainly isoflavonoids but also lignans), as well as whole grain cereals, seeds, probably berries and nuts (mainly lignans). The plant lignan and isoflavonoid glycosides are converted by intestinal bacteria to hormone-like compounds with weak estrogenic and antioxidative activity; they have now been shown to influence not only sex hormone metabolism and biological activity but also intracellular enzymes, protein synthesis, growth factor action, malignant cell proliferation, differentiation and angiogenesis, making them strong candidates for a role as natural cancer protective compounds. Epidemiological investigations support this hypothesis, because the highest levels of these compounds are found in countries or regions with low cancer incidence. This report is a review of results that suggest that the diphenolic isoflavonoids and lignans are natural cancer-protective compounds.

ICAM-1 induction on hepatocytes as a marker for immune activation of acute liver allograft rejection.

Intercellular adhesion molecule-1 (ICAM-1) induction on hepatocytes was investigated in relation to acute liver allograft rejection, CMV infection, and systemic bacterial infections. Twenty-four liver transplant recipients underwent an episode of acute rejection, 13 developed a symptomatic clinical CMV infection, and 7 had bacterial sepsis. Seven recipients without rejection or infection complications were used as controls. All rejection episodes monitored by frequent FNABs were reversible, and lymphocyte and lymphoid blast-dominated with a with peak of inflammation (7.2 +/- 3.9 corrected increment units [CIU]). The rejections were treated with high-dose steroids, and the inflammation subsided within one week. ICAM-1 was demonstrated from fine needle aspiration biopsy (FNAB) preparations by a monoclonal antibody and immunoperoxidase staining. ICAM-1 was not detected on the hepatocytes immediately after transplantation or in control patients, but was always seen during rejection. ICAM-1 appeared 1-5 days before the onset of inflammation in FNAB. The intensity of ICAM-1 expression increased toward the peak of inflammation and subsided together with inflammation. During CMV infection a mild immune activation was seen in FNAB (peak 2.5 +/- 0.8 CIU) and in blood. An intense ICAM-1 induction also preceded the immune activation caused by CMV, and subsided slowly with successful antiviral treatment. In addition, a slight ICAM-1 induction on the hepatocytes was recorded during bacterial sepsis. ICAM-1 induction on hepatocytes appears to be linked with an early phase of immune response, and it even precedes the lymphoid activation of rejection. However, several infections, such as CMV and bacterial infections, raise an immune response and may also induce ICAM-1. In conclusion, ICAM-1 induction on hepatocytes can be considered an early, though unspecific, marker for acute liver allograft rejection.

Acute vascular rejection in renal transplantation--diagnosis and outcome.

Thirty episodes of histologically verified acute vascular rejection in kidney transplant recipients were studied. In 11 grafts the rejection was mainly vascular, whereas in 19 grafts a concomitant cellular rejection was seen. Histological features prognostic for bad outcome were glomerular necrosis and thrombi in the arteries and arterioles. Characteristic findings in transplant cytology, i.e., high number of monocytes and low number of lymphocytes and blast cells were noted prior to the onset of clinical signs of rejection, and this finding was also persisting throughout the rejection episode. The numbers of lymphocytes and blast cells were significantly lower in grafts with a pure vascular rejection than in grafts with a concomitant cellular rejection. Vascular rejection was reversible in 15 cases. As rescue therapy plasmapheresis and added immunosuppression were often successful.

Peripheral and liver tissue oxygen tensions in hemorrhagic shock.

BACKGROUND AND METHODS: Hepatic dysfunction after severe hemorrhagic shock is common and may be a consequence of visceral tissue hypoxia. Peripheral tissue PO2 has been suggested to correlate with the development of visceral hypoxia. To test the hypothesis that changes in peripheral tissue PO2 reflect changes in hepatic PO2, we measured subcutaneous PO2, transcutaneous PO2, transconjunctival PO2, and liver tissue PO2, and their relationship with changes in mean arterial blood pressure (MAP) and systemic oxygen transport (DO2), during progressive bleeding in pigs (n = 23). In addition to the tissue PO2, portal vein PO2 and circulating lactate concentrations were also measured in six of the animals. The animals were anesthetized and bled to an MAP of 50 mm Hg within 1 hr. RESULTS: After an induced 10% reduction of MAP, only the DO2 decreased significantly (p less than .05). After a 20% reduction of MAP, the DO2 decreased further and was associated with a significant (p less than .05) reduction of all peripheral tissue PO2 values. A significant (p less than .05) reduction of liver tissue PO2 was observed later during bleeding, after induction of a 30% reduction in MAP. In the subgroup with portal venous PO2 and lactate measurements, reductions of all peripheral tissue PO2 and portal venous PO2 values occurred after a 20% reduction (p less than .05) of MAP. An increase (p less than .05) in the portal venous lactate concentration was observed after a 50% reduction of MAP, and a decrease (p less than .05) in liver tissue PO2 was noted after a 60% reduction of MAP. CONCLUSIONS: Reductions of both peripheral and portal venous PO2 values occur early during hemorrhage. The liver tissue PO2, though initially low, appears to be better defended, suggesting either redistribution of splanchnic blood flow or adaptation in hepatic oxygen demand.

Effects of bicarbonate therapy on tissue oxygenation during resuscitation of hemorrhagic shock.

We investigated the effects of clinically appropriate doses of NaHCO3 on tissue oxygenation when hemorrhagic shock was corrected with hydroxyethyl starch (hetastarch) in 12 piglets. Six animals received colloid only while six received colloid and bicarbonate. Both groups recovered rapidly hemodynamically, but conjunctival, subcutaneous, and liver tissue PO2 values returned to baseline more slowly after bicarbonate administration. In the NaHCO3 group, pulmonary artery wedge pressure and arterial bicarbonate concentration were higher during early resuscitation, and arterial plasma lactate remained higher than in the control group at the end of the follow-up period. The delayed increase in tissue PO2 values after bicarbonate infusion may be explained, at least partly, by decreased arterial blood oxygenation and a shift of the oxyhemoglobin curve to the left. NaHCO3 adjunct has no added beneficial effect on hemodynamics and may be harmful to tissue oxygenation in hemorrhagic shock resuscitated with hetastarch.

Correction of hemorrhagic shock-induced liver hypoxia with whole blood, Ringer's solution or with hetastarch.

Liver oxygenation was studied with hemorrhagic hypotension and corrected using whole blood, a synthetic colloid (hydroxyethyl starch or hetastarch, HES; mol. wt. 120,000), or a crystalloid solution. Measurements were performed directly by recording pig liver tissue oxygen tension with an implanted silicone elastomer (Silastic) tube, and indirectly by calculating blood oxygen contributions. The direct method seems fairly reliable and accurately reflects different levels of bleeding and shock and their correction. Liver tissue oxygen tension (PlO2) may thus be used as an indicator of central organ response to shock management. PlO2 decreased during bleeding from 33.5 +/- 0.5 to 16.0 +/- 0.5 torr, and normalized rapidly after retransfusion. The baseline values were significantly exceeded after hetastarch infusion but were never reached with Ringer's solution. The correction of liver oxygen consumption was less complete after crystalloid infusion as well. On the other hand, the difference in liver oxygenation was less marked after crystalloid infusion and retransfusion, which restored perfusion to the baseline. The total amount of Ringer's solution needed to keep the animals hemodynamically stable during the 2-h follow-up period was four times higher than with hetastarch and some five times the blood volume shed. The cause of defective correction of liver oxygenation seems to be the poor response of liver blood flow to refilling in the Ringer group, in addition to apparent tissue edema after crystalloid infusion. According to our study, hemorrhagic hypotension related to liver oxygenation is more promptly and completely corrected with the colloid hydroxyethyl starch than with a crystalloid solution in the early phase of treatment.

Subcutaneous and liver tissue oxygen tension in hemorrhagic shock: an experimental study with whole blood and two colloids.

Because it is difficult to verify the efficacy of hemorrhagic shock treatment, we compared subcutaneous O2 tension (PscO2) with liver oxygenation in efforts to correct shock in piglets with two different colloids, hydroxyethyl starch (HES-120) and dextran-70. Nineteen animals were bled to shock and the shed blood was retransfused in the control group. Liver oxygenation was measured directly by means of a silicone tube used as a tonometer, and indirectly by calculating liver O2 consumption (VO2). PscO2 was monitored with a needle electrode. The two colloid groups were compared by measuring plasma lactate, and the plasma colloid osmotic pressure (COPp). PscO2 followed closely the changes in liver tissue PO2 during the experiment; it seems to be a useful tool in estimating volume filling during the treatment of hemorrhagic shock. A wider variation was noted in calculated liver VO2 compared with hepatic venous PO2 or liver tissue PO2. Despite the fact that COPp increased to a higher level after the administration of dextran, HES proved to be at least as effective as dextran in restoring mean arterial pressure, cardiac output, liver oxygenation, PscO2, arterial pH, arterial plasma lactate, and liver lactate uptake.