Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Critical preservation injury in rat fatty liver is to hepatocytes, not sinusoidal lining cells.

BACKGROUND: Fatty livers are more prone to primary nonfunction after transplantation. We hypothesized that sinusoidal lining cells (SLCs) in fatty livers of obese Zucker rats are more susceptible to ischemia/reperfusion injury than in normal livers. METHODS: Cold University of Wisconsin solution-preserved (30 min or 24 hr) livers from obese and lean Zucker rats were perfused ex vivo for 90 min with oxygenated warm acellular buffer containing hyaluronate. Bile output, alanine transferase, and hyaluronate clearance were measured during reperfusion. Trypan blue was infused at completion of reperfusion to assess cell membrane integrity. Another group of 24-hr preserved livers were reperfused with cold hypoxic buffer to differentiate the effects of preservation from reoxygenation. RESULTS: After 30 min of preservation, fatty livers had significantly decreased flow (1.9 vs. 2.6 ml/g/min), increased resistance, decreased hyaluronate clearance (17 vs. 35 microg/g liver) and lower bile output (13 vs. 42 microl/g) in comparison with normal livers. Hepatocyte and SLC trypan blue uptake were minimal and similar in both groups. After 24 hr of preservation, flow (2.0 vs. 2.0), resistance, hyaluronate clearance, and bile output were similar in both fatty and normal livers. The SLC trypan blue uptake was increased but similar in both groups (22 vs. 20%). In contrast, a significantly greater number of hepatocytes were trypan blue-stained in fatty livers (32 vs. 0.6%), accompanied by a marked increase in lactate dehydrogenase and alanine transferase release. Hypoxic reperfusion caused a significant decrease in hepatocyte and SLC trypan blue uptake. CONCLUSIONS: Fatty livers demonstrate impaired hepatocyte and SLC function, after even a very brief preservation. With increasing preservation, hepatocytes appear to be more susceptible to injury than SLCs. Reoxygenation appears to be important in triggering this event.

31P nuclear magnetic resonance study of phospholipids in ischemia/reperfusion injury in a rat fatty liver model.

Obese Zucker rats are susceptible to increased hepatic ischemia/reperfusion (I/RP) injury. Increased lipid peroxidation occurs in this model with warm ischemia. We hypothesized that a severe depletion of phospholipids (PL) occurs with warm I/RP in fatty livers. Obese (Ob) and lean (Ln) Zucker rats were subjected to 90 min of in vivo partial hepatic warm I followed by RP. Total lipids extracted from one gm of liver (median lobe) taken at the end of 1, 2 and 6 hr of RP and sham (Sh) surgery (n=5 Ln & Ob) were analyzed by 202.3 MHz 31P NMR, which provided good resolution of individual PL. Obese (Sh) rats contained 22% more PL than Ln (P= < 0.01). Ischemia caused similar decreases in PL in both Ob (to 67% Sh) and Ln rats (62%). Following 2 hr RP, PL in Ob rats decreased further (46% Sh) and recovered only marginally at 6 hr (53%), in marked contrast to the rapid recovery in Ln to preischemic levels (110% Sh at both 2 and 6 hr; P=<0.001). Mole percents of individual PL did not change significantly except for lysophosphatidylcholine, which increased from 0.43 to 1.3% (Sh vs. 6 hr RP) in the Ob, but decreased from 0.98 to 0.52% in Ln animals (P = <0.001). Fatty livers thus are more vulnerable to phospholipid depletion in response to warm ischemia/reperfusion than normal livers.

Studies of hepatic warm ischemia in the obese Zucker rat.

The effects of warm ischemia were investigated in obese Zucker rats with severe hepatic steatosis in order to develop a nontransplant fatty liver ischemia model. Obese (Ob) and lean (Ln) Zucker rats were subjected to in vivo partial hepatic warm ischemia of 45 or 90 min. Injury was assessed by serum alanine aminotransferase, animal survival, and liver histology. Liver lipids were quantified in control animals. After 90-min ischemia and 2-hr reperfusion, liver malondialdehyde was measured and neutrophils in 12 microscopic fields were counted after esterase staining. After 45 and 90 min of ischemia, Ob animals had significantly higher alanine aminotransferase at 1-hr and 24-hr reperfusion, compared with Ln animals (P < 0.01). After 90 min of ischemia, none of the Ln and 8/9 Ob animals died within 48 hr (P < 0.01). Histologically, Ob animals had more hepatocyte necrosis than did Ln animals. Hepatic neutral and phospholipid content (mg/g) in Ob versus Ln animals was 45.2 +/- 2.6 versus 8.2 +/- 0.7 (P < 0.01) and 36.2 +/- 1.9 versus 27 +/- 2.2 (P < 0.05), respectively. After reperfusion, liver malondialdehyde content increased significantly in Ob animals (8.5 +/- 0.4 vs. 12.3 +/- 0.8 pM/mg protein; P < 0.05), but not in Ln animals. Neutrophils, scant in control livers, increased significantly (P < 0.01) after ischemia/RP, but it increased to a similar degree in Ob and Ln animals. Obese Zucker rats with hepatic steatosis are more susceptible to warm ischemia/reperfusion injury than lean animals, and lipid peroxidation may be an important contributory mechanism. Further studies in this model might help to investigate the human problem.

Hepatic artery thrombosis after pediatric liver transplantation--a medical or surgical event?

Hepatic artery thrombosis (HAT) is one of the most serious complications after orthotopic liver transplantation, and is associated with a high morbidity and mortality. This study retrospectively reviewed 66 liver transplants in children under the age of 10 years during a year-long period at a single institution. A total of 28 perioperative variables were analyzed to identify responsible factors of HAT. Of the 66 children, 18 (26%) developed HAT within 15 days after the transplant (HAT group); 29 (42%) had an uneventful postoperative course (control group). To avoid the possible influence of other complications 19 patients were excluded. Of the variables compared between the 2 study groups, three surgical factors (diameter of the hepatic artery--greater or less than 3 mm; type of arterial anastomosis--end-to-end versus the use of an iliac graft or aortic conduit; and number of times the anastomosis was redone--one versus more than one), were found to be significantly different (P less than .05) between HAT and control groups. Two medical factors also were significantly different: the use of intraoperative transfusion of fresh frozen plasma (FFP) and the administration of postoperative prophylactic anticoagulant treatment. A heparin and dextran-40 protocol appeared to be effective in preventing HAT (P less than .02). Moreover, after multivariate analysis, anticoagulation therapy was demonstrated to be the major independent variable influencing HAT. A better definition of factors responsible for the occurrence of HAT is required. This study should help in formulating effective methods to decrease the incidence of this dreaded complication after liver transplantation.

Blood transfusions in liver recipients: a conundrum or a clear benefit in the cyclosporine/tacrolimus era?

Blood transfusions are common in patients with end-stage liver disease (ESLD), and their effects on sensitization, rejection, and liver graft survival are not well known. These effects were examined in 121 recipients of primary liver grafts, surviving > or = 30 days. Ninety-six (79%) patients received transfusions before transplantation. Transfusion recipients had significantly fewer severe or recurrent rejection episodes (18%), compared with patients who did not receive transfusions (42%, P=0.006), if the first transfusion was > or = 90 days before the transplant. Patients with alcoholic ESLD (n=49) had significantly fewer severe rejection episodes when compared with the nonalcoholic (n=72) patients (12% vs. 35%, P=0.004). The transfusion benefit was, however, more apparent and significant in the nonalcoholic (26% vs. 56% in nontransfused, P=0.02) than among the alcoholic recipients (6% vs. 25%, P=0.1). This finding is, most likely, due to a combination of a higher rate of severe rejection and the statistical power of the larger number of recipients in the nonalcoholic group. This finding is further corroborated by a multivariate analysis in which blood transfusions retained their benefit (P<0.05) independent of recipient's age and diagnosis. Graft and patient survival were not significantly different in the transfused versus nontransfused groups. Transfusion recipients had a higher panel antibody (11.4+/-23.4 vs. 2.7+/-8.1, P<0.02) but no increased risk of a positive crossmatch. In liver recipients, blood transfusions diminish the risk of rejection independent of recipient's age and the cause of ESLD.

Childbearing after liver transplantation.

Seventeen female patients who underwent orthotopic liver transplantation between June 1973 and June 1987 became pregnant 5 months to 11 years after transplantation. Immunosuppression was maintained with combinations of prednisone, cyclosporine, and azathioprine prior to and during pregnancy. One patient discontinued immunosuppression after knowledge of pregnancy, taking only azathioprine sporadically. Mean age at time of delivery was 26 years. Twelve patients had no alteration in liver function studies; 7 patients demonstrated mild or moderate enzyme elevations prior to delivery, with one case of rejection confirmed by percutaneous liver biopsy. Major problems related to pregnancy were hypertension, anemia, and hyperbilirubinemia. Twenty live births occurred (2 patients had 2 separate pregnancies, one patient had a set of twins); 13 were by cesarean section, 7 by vaginal delivery. Eleven of the 13 cesarean births were premature by gestational age. All vaginal births were term. Toxemia of pregnancy and early rupture of membranes were the principal indications for cesarean section. There were no congenital abnormalities or birth defects and all the children are surviving well. Fifteen of 16 children older than one year all have normal physical and mental development, with one child manifesting immature speech development. Four children are under one year, all with normal milestones thus far. Sixteen of the 17 mothers are alive from 2-18 years after transplantation; the only death was from a lymphoma, almost 4 years after transplantation and 2 1/2 years after delivery. This experience suggests that women undergoing liver transplantation can safely bear children despite an increased risk of premature cesarean births. The effect of chronic immunosuppression of female pediatric patients on their reproductive potential later in adulthood remains to be fully evaluated but the results so far are favorable.

Liver transplantation in the treatment of bleeding esophageal varices.

From March 1980 to July 1987, 1000 patients with various end-stage liver diseases received orthotopic liver transplants. Of the 1000 patients, three hundred two had definite histories of bleeding from esophageal varices before transplantation. There were 287 patients with nonalcoholic liver diseases and 15 patients with alcoholic cirrhosis. All patients had very poor liver function, which was the main indication for liver transplantation. One- through 5-year actuarial survival rates of the 302 patients were 79%, 74%, 71%, 71%, and 71%, respectively. These survival rates are far better than those obtained with other available modes of treatment for bleeding varices when liver disease is advanced. Long-term sclerotherapy is the treatment of primary choice for bleeding varices. Patients in whom sclerotherapy fails should be considered for liver transplantation unless clear contraindications exist.

Nonobstructing colonic dilatation and colon perforations following renal transplantation.

Nonobstructing colonic dilatation has not been commonly reported following renal transplantation, and colon perforations carry a high morbidity and mortality in this population. During a 7-year period, nonobstructing colonic dilatation developed in 13 adults 1 to 13 days after renal transplantation. Twelve (92%) of the 13 had poorly functioning allografts. Five (83%) of the 6 with and 2 (29%) of the 7 without colonoscopy had resolution of nonobstructing colonic dilatation. Of the seven right-sided colon perforations during this period, six were associated with nonobstructing colonic dilatation. An additional 4 patients had diverticular perforations in the left colon. Of a total of 11 patients with colon perforation, 7 had surgery within 24 hours of the perforation and 6 (86%) of these survived. Only 1 (25%) of the 4 having surgery more than 24 hours later survived. Six of the survivors retained functioning allografts. Nonobstructing colonic dilatation seems to be a potential complication of poor graft function after renal transplantation, and colonoscopy is effective in its treatment. In patients with colon perforations, early surgery and reduced immunosuppression are essential in decreasing mortality.

Effect of increasing gastric pH with famotidine on the absorption and oral pharmacokinetics of the inotropic agent vesnarinone.

The effect of famotidine, an H2 receptor blocker, on the oral absorption and pharmacokinetics of the novel agent vesnarinone was investigated after oral administration of 60 mg vesnarinone with and without pretreatment with intravenous famotidine. The single-blind, randomized, two-way crossover study was conducted in 12 volunteers, with a washout period of 7 days between the two treatments. A pH monitor was used to ensure that gastric pH of the subjects was < or = 3 in the absence of and > or = 5 in the presence of famotidine. A significant decrease in maximum concentration (Cmax) and increase in time to Cmax (tmax) was observed for vesnarinone during treatment with famotidine, whereas area under the concentration-time curve (AUC) was similar for both treatments. The physicochemical properties of the drug support the above observations. Therefore, therapies that increase gastric pH will affect the rate but not the extent of absorption of vesnarinone or the safety or efficacy profile of vesnarinone.

Biliary tract complications in orthotopic adult liver transplantation.

In a series of orthotopic liver transplantations performed between April and August 1987 at the University of Pittsburgh, the monofilament absorbable suture polyglyconate was compared with a braided absorbable suture, polyglactin 910, for its biliary complication rate over a 6-month postoperative period. Complications that were suture-related (obstruction or leak from the anastomotic site) occurred in 1 of 21 transplantations in the polyglyconate group compared with 8 of 26 in the polyglactin 910 group (p = 0.02). Even though the patient sample was relatively small, it appears that the type of suture used for the biliary anastomosis directly correlates with the outcome. A larger patient trial could confirm these initial results.

C282Y mutation and hepatic iron status in hepatitis C and cryptogenic cirrhosis.

BACKGROUND: Increased iron deposition in liver is seen in both primary and secondary hemochromatosis. However, it is not uncommon to see significant iron deposition in a liver biopsy, explant, or autopsy specimen without any significant clinical risk factor. Because of the discovery of the candidate gene (HFE) for hereditary hemochromatosis, we may now be able to screen high-risk patient populations for the abnormal mutation (C282Y). MATERIALS AND METHODS: In this study we analyzed the livers of 50 transplant patients with a diagnosis of either hepatitis C cirrhosis or cryptogenic cirrhosis for the prevalence of the more common C282Y mutation of the HFE gene and correlated the findings to hepatic iron concentration. RESULTS: Of the 26 cases of hepatitis C cirrhosis, 3 were found to be heterozygous for the C282Y mutation. Of the 22 cases of cryptogenic cirrhosis, 1 was found to be heterozygous for the C282Y mutation. Stainable iron was increased in hepatitis C cirrhosis (76.9%) as compared to cryptogenic cirrhosis (50%) (P =. 05). Of the 3 heterozygotes with hepatitis C cirrhosis, 2 showed hepatic iron concentrations of 3+ and 4+, and 1 showed 1+. CONCLUSIONS: We conclude that patients with hepatitis C have an increased tendency to accumulate iron in the liver, and mutations in the HFE gene play a minor role in hepatic accumulation of iron in these patients.

Orthotopic liver transplantation for alpha-1-antitrypsin deficiency: an experience in 29 children and ten adults.

Thirty-nine patients (29 children and ten adults) underwent OLT for liver disease associated with A1AD from March 1980 to March 1986. Thirty of thirty-six patients (83%) with available data were homozygous phenotype PiZZ. The other six were Pi heterozygotes, being either PiMZ or PiSZ. The mean A1A activity in homozygous and heterozygous patients was 38.8 mg/dL and 114.3 mg/dL respectively. Eight patients died during the first 3 months after OLT (20%). The 5-year actuarial survival is 83% and 60% in pediatric and adult recipients respectively. Today 30 (76%) of the recipients are alive, with follow-ups of 8 to 64 months (average 27 months). The quality of life in the surviving patients is excellent.

Deceptive prothrombin and activated partial thromboplastin times in alcoholic cirrhosis.

It is believed that perioperative hemorrhage, in the hepatoportal area, results from a coagulopathy. This study determined if this could be quantitated by a modified recalcification time (MRT) test developed in our laboratory. Unlike prothrombin (PT) and activated partial thromboplastin times (APTT), the MRT is performed with whole blood to ensure the role of blood cells and chemicals (particularly tissue factor, a potent procoagulant) in the coagulation process. Candidates for liver transplantation (n = 11) were studied. Samples (5 mL) of citrated venous blood were obtained from the patients. Aliquots (1 mL) from these samples were divided into groups of vials labeled C, S, and E. Groups C and S received 20 microL saline and group E, 20 microL of saline containing 10 micrograms of Escherichia coli endotoxin (055: B5W). Vial C was incubated for 10 minutes and vials S and E for 120 minutes, all at 37 degrees C. Then, the MRT was determined on 300 microL of blood from each vial after adding 40 microL of 0.1M calcium chloride. Mean MRT values (minutes +/- standard deviation) for C (MRTC), for S (MRTS), and for E (MRTE) were compared with like values from healthy controls (n = 29). Despite prolonged PT and APTT values, MRT values were shortened in patients with cirrhosis. This hypercoagulability detected by the MRT exonerates a hemorrhagic coagulopathy and possibly implicates widened and thinned gaps in the walls of the portal venous tributaries as the cause of perioperative hemorrhage.

New Jersey research: frontiers of hepatology.

Diagnostic criteria and prognosis have been revised for patients with liver and biliary tract diseases. This information provides an improved knowledge base for new preventive measures, therapeutic modalities, and outcome research at UMDNJ-New Jersey Medical School Liver Center.

The first 50 liver transplants in New Jersey.

New Jersey's first liver transplant was performed on February 14, 1989, at UMDNJ-New Jersey Medical School. By May 1992, 50 patients, ranging in age from 16 to 65 years, had been transplanted. Liver transplantation is an accepted method of treatment for end-stage liver disease.