Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression.

We studied the clinical features, blood levels of cyclosporine, and neuroimaging findings in 46 patients with cyclosporine neurotoxicity after liver transplantation. The clinical presentation of cyclosporine neurotoxicity was characterized by tremulousness and restlessness in all patients and was associated with acute confusional state and psychosis in 20 patients, seizures in eight, speech apraxia or action myoclonus speech in three, and cortical blindness in two. In 35 patients, cyclosporine neurotoxicity occurred during IV treatment. Neuroimaging studies showed only minor white matter abnormalities in two patients despite dramatic clinical presentations, including speech difficulties, seizures, and cortical blindness. In only 19 of 31 patients (61%) did trough levels of cyclosporine suggest neurotoxicity. Neurologic findings were reversible in all patients after cyclosporine was withheld and then given in lower dosage. In three patients, substituting FK 506 did not result in neurotoxicity.

An increase in cytosolic protease activity during liver preservation. Inhibition by glutathione and glycine.

Degradative cytosolic proteolysis contributes to cell injury following ATP depletion. Although ATP depletion is a salient feature of ischemic liver storage for transplantation, information regarding cytosolic protease activity during liver storage is lacking. Thus our aim was to measure liver cytosolic protease activity following ischemic storage. A progressive increase in total cytosolic protease activity was observed over time at both 37 degrees C and 4 degrees C, but the increase was greater at 37 degrees C. Total cellular proteolysis was also temperature-dependent during anoxia (37 degrees C > 4 degrees C), demonstrating a physiologic correlation between cellular proteolysis and measurements of cytosolic protease activity. The stimulation of total cytosolic protease activity was due to an increase in metallo- and aspartate protease activity. Of particular interest, glutathione (GSH) inhibited both metalloprotease and aspartate protease activity from cytosol of stored livers. Glycine, the carboxyl-terminal amino acid of GSH, also inhibited both metalloprotease and aspartate protease activity. In addition to being an antioxidant, GSH may exert its protective effects during organ preservation by inhibiting cytosolic proteases--perhaps via its glycine moiety. These experiments support the hypothesis that degradative proteolysis contributes to liver injury during organ preservation.

Splenic artery aneurysms in liver transplant patients.

We found splenic artery aneurysms in 6 of 71 consecutive patients who underwent orthotopic liver transplantation at the Mayo Clinic. The incidence of splenic artery aneurysms in cirrhotic patients with portal hypertension was 10%. Five of the aneurysms were found in patients suffering from chronic active hepatitis, whereas no aneurysms were encountered in patients with primary sclerosing cholangitis or primary biliary cirrhosis. One patient ruptured a splenic artery aneurysm shortly after liver transplantation, and 1 patient developed an aneurysm 3 months after transplantation. We recommend coeliac angiography to be performed prior to liver transplantation, and if splenic artery aneurysms are found, ligation of the splenic artery should be performed at the time of transplantation to prevent possible rupture.

Enhanced liver calpain protease activity is a risk factor for dysfunction of human liver allografts.

Our aim was to determine whether calpain protease activity is increased in liver tissue from allografts that have poor graft function postoperatively. Liver tissue was obtained from 36 patients at 1 hr after recirculation. The patients were divided into two groups: (1) 30 patients with good graft function; and (2) six patients with immediate poor graft function. Calpain protease activity was increased 1.6-fold in biopsy specimens from patients with immediate poor function as compared with those with excellent graft function. There was no difference between the two groups with regard to cold ischemic time for organ storage, donor age, recipient age, United Network for Organ Sharing status of the recipient, or fatty infiltration of the donor liver. In summary, enhanced calpain protease activity present in the liver 1 hr after reperfusion is a risk factor for graft dysfunction.

Soluble interleukin-2 receptor level as an indicator of liver allograft rejection.

We studied the serum levels of soluble interleukin-2 receptors (SIL-2R) in liver allograft recipients: a control group without rejection or CMV disease, a group with only rejection episodes, and a group with only cytomegalovirus disease. Rejection was diagnosed by the presence of compatible laboratory and histologic abnormalities and absence of other causes of graft dysfunction. CMV disease was diagnosed by isolation of CMV in blood or liver specimen cultures or identification of cytomegalic inclusions in the liver biopsy specimen. Of 82 consecutive recipients treated with cyclosporine and prednisone, 12 were in the control group, 20 in the rejection group, and 5 in the CMV disease group. The remaining 45 had other or multiple complications. In the control group the SIL-2R levels (determined by an ELISA) decreased by a mean of 4% per day after transplantation; in the rejection group the levels increased by a mean of 17% per day in the 10 days prior to the diagnosis of rejection; in the CMV disease group the levels tended to increase prior to the diagnosis of CMV disease. The rejection group had significantly higher SIL-2R levels than the control group at comparable times. Thus, SIL-2R levels were significantly increased at the time of allograft rejection compared with levels in a control group, and recipients with CMV disease had increased levels of SIL-2R but they were not as high as in recipients with rejection episodes.

Cytomegalovirus and its association with hepatic artery thrombosis after liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) is a cause of morbidity and graft loss in approximately 7% of patients after an orthotopic liver transplantation (OLT). Although technical problems are often thought to be the cause of HAT, in general the etiology remains unclear. Because cytomegalovirus (CMV) can infect endothelial cells in vitro and lead to a rapid procoagulant response, it can be hypothesized that, in the absence of CMV antibodies, latent CMV in an allograft may become activated and promote or contribute to vascular thrombosis. Therefore, the purpose of this study was to examine the relationship between CMV serology of the donor and recipient with the development of HAT after OLT. METHODS: Between July 1988 and November 1995 (University of Wisconsin era), 490 OLTs were performed in 413 patients. Subsequently, four patients were excluded in whom the CMV serology results of the donor were not available. Sixteen of the 409 patients developed HAT within 30 days after liver transplantation. The control group consisted of the other 393 patients. RESULTS: The incidence of HAT was 12.5% in 64 CMV D+R- patients and 0% in 52 CMV D-R- patients. However, in the other combinations (D+R+ and D-R+), the incidence was only 2.8% (P = 0.005). Eight of the 16 patients with HAT belonged to the CMV D+R- group. CONCLUSIONS: We conclude that CMV-seronegative patients receiving a seropositive allograft may be at risk for early HAT. Seropositivity of the donor alone and of the recipient alone was not significantly related to the incidence of HAT. Prophylactic treatment with ganciclovir and/or anticoagulation should be evaluated to prevent this complication.

Early allograft dysfunction after liver transplantation: a definition and predictors of outcome. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.

BACKGROUND: Poor graft function early after liver transplantation is an important cause of morbidity and mortality. We defined early allograft dysfunction (EAD) using readily available indices of function and identified donor, graft, and pretransplant recipient factors associated with this outcome. METHODS: This study examined 710 adult recipients of a first, single-organ liver transplantation for non-fulminant liver disease at three United States centers. EAD was defined by the presence of at least one of the following between 2 and 7 days after liver transplantation: serum bilirubin >10 mg/dl, prothrombin time (PT) > or =17 sec, and hepatic encephalopathy. RESULTS: EAD incidence was 23%. Median intensive care unit (ICU) and hospital stays were longer for recipients with EAD than those without (4 days vs. 3 days, P = 0.0001; 24 vs. 15 days, P = 0.0001, respectively). Three-year recipient and graft survival were worse in those with EAD than in those without (68% vs. 83%, P = .0001; 61% vs. 79%, P = 0.0001). A logistic regression model combining donor, graft, and recipient factors predicted EAD better than models examining these factors in isolation. Pretransplant recipient elevations in PT and bilirubin, awaiting a graft in hospital or ICU, donor age > or =50 years, donor hospital stay >3 days, preprocurement acidosis, and cold ischemia time > or =15 hr were independently associated with EAD. CONCLUSION: Recipients who develop EAD have longer ICU and hospital stays and greater mortality than those without. Donor, graft, and recipient risk factors all contribute to the development of EAD. Results of these analyses identify factors that, if modified, may alter the risk of EAD.

Influence of positive lymphocyte crossmatch and HLA mismatching on vanishing bile duct syndrome in human liver allografts.

Among the first 52 recipients of primary liver allografts with follow-up of 2 weeks or greater, 6 patients had biopsy-confirmed vanishing bile duct syndrome (VBDS) and required retransplantation. Five of these six patients had positive lymphocyte crossmatches. Of the 46 remaining liver transplant recipients, 11 had positive crossmatches. Thus, the incidence of VBDS was 5/16 in recipients with a positive crossmatch and 1/36 in recipients with a negative crossmatch. The positive-crossmatch group was significantly more likely to develop VBDS than the negative-crossmatch group (P less than 0.004, log rank test). Additional HLA studies comparing degree of donor-recipient mismatch at the various HLA loci showed no significant difference between the groups for class I disparity. However, class II mismatch was of borderline significance (P less than 0.056). When evaluated individually, the DQ mismatch (P less than 0.04) appeared to be more important than the DR mismatch (P = NS). Our data suggest that a positive lymphocyte crossmatch and a class II mismatch, in particular HLA DQ disparity, may play an important role in the pathogenesis of VBDS.

Selective bowel decontamination to decrease gram-negative aerobic bacterial and Candida colonization and prevent infection after orthotopic liver transplantation.

Gram-negative bacterial and fungal infections are a major cause of morbidity and mortality following liver transplantation. We therefore used selective bowel decontamination (SBD) to eliminate the endogenous source of gram-negative aerobic bacteria and Candida pathogens in an attempt to reduce the high incidence of infection related to these organisms. Thirty consecutive patients undergoing liver transplantation were treated with SBD starting 3 days prior to donor search and continuing for 21 days postliver transplantation. Selective bowel decontamination consisted of administering nonabsorbable antibiotics (Polymixin E, gentamicin, Nystatin) and a low bacterial diet. Surveillance cultures of the throat and rectum were obtained to monitor efficacy of selective bowel decontamination. In addition, in the posttransplant period, tracheal, wound, blood, and bile cultures were obtained to screen for gram-negative bacterial and Candida colonization and infection. Our baseline surveillance culture revealed that 29/30 (97%) of recipients were colonized with gram-negative aerobic bacteria and 16/30 (53%) with Candida. Three days after selective bowel decontamination was started, 26/30 (87%) were free of gram-negative bacteria, and 100% were free of Candida colonization of the gastrointestinal tract. There was a similar reduction in the oropharyngeal gram-negative aerobic bacteria and Candida colonization. In the first 30 days following liver transplantation, gram-negative infections were not diagnosed in any of our patients. Following discontinuation of SBD, recolonization of the gastrointestinal tract with gram-negative aerobic bacteria and Candida occurred within 5 days in 26/28 (90%) and 11/28 (35%), respectively. Our study suggests that prophylactive administration of nonabsorbable antibiotics will markedly reduce gram-negative aerobic bacterial and Candida colonization and appears to reduce the high incidence of infection related to these organisms in the early posttransplant period.

Efficacy of ganciclovir in liver and kidney transplant recipients with severe cytomegalovirus infection.

Twelve liver and 5 kidney transplant recipients with severe cytomegalovirus infection were treated with Ganciclovir (7.5 mg/kg/day, intravenously). Ten were evaluable (compatible clinical picture, organ involvement shown histopathologically or by culture, viremia, and absence of concomitant infection). All 17 patients were studied for adverse drug side effects. A total of 9 evaluable patients survived the infection; 1 died during treatment due to infection or drug toxicity. A death 19 days after completion of treatment was due to unrelated causes. Patients became afebrile after 2-9 days (mean, 5.3 days) of treatment. Liver function improved, pulmonary infiltrates cleared, and hypoxemia reversed during therapy. Viremia ceased during therapy in 9 patients; asymptomatic viruria persisted or recurred in 6 of 7 patients studied. No relapses occurred during follow-up (7-17 months; mean, 13 months). Transient neutropenia and thrombocytopenia occurred in 3 and 1 patients, respectively. Ganciclovir appears promising for treatment of severe CMV infection in patients with kidney or liver transplants.

Comparative allograft histology after liver transplantation for cryptogenic cirrhosis, alcohol, hepatitis C, and cholestatic liver diseases.

BACKGROUND: End-stage liver disease for which no cause can be identified, cryptogenic cirrhosis, is a common indication for liver transplantation. Allograft inflammation and fibrosis have been reported to recur with similar frequencies after liver transplantation for cryptogenic cirrhosis and hepatitis C (HCV). METHODS: We determined sequential posttransplant allograft histology in four groups of recipients: 31 transplanted for cryptogenic cirrhosis, 70 for cholestatic etiologies, 40 for alcoholic liver disease, and 56 for HCV. Modified hepatitis activity index (HAI) and fibrosis stage were determined at 4 months, 1 year, and at most recent biopsy posttransplantation. RESULTS: The prevalence of HAI > or = 2 among cryptogenic recipients was similar to that of cholestatic and alcoholic recipients at 4 months, 1 year, and at most recent evaluation (mean 45+/-17 months posttransplantation). For HCV-infected recipients, the frequency of HAI > or = 2 was more than for cryptogenic recipients at 1 year (52 vs. 29%, P=0.04) and at most recent evaluation (64 vs. 15%, P=0.003). Fibrosis scores for cryptogenic, cholestatic, and alcoholic recipients were similar at all timepoints. The proportion of HCV-infected recipients with fibrosis stage >2 was more than that of cryptogenic recipients at 4 months (29 vs. 12%, P=0.05), 1 years (46 vs. 7%, P=0.0002), and at most recent evaluation (42 vs. 15%, P=0.06). None of the cryptogenic recipients developed cirrhosis. RESULTS: The frequency of elevated HAI and fibrosis stage in recipients who undergo transplantation for cryptogenic cirrhosis is similar to that of recipients who undergo transplantation for cholestatic etiologies and significantly less than that of HCV-infected recipients. Fibrosis stage and HAI are generally stable after transplantation for cryptogenic cirrhosis. These data do not suggest a viral etiology of liver disease in the majority of patients with cryptogenic cirrhosis.

Renal hemodynamics, urinary eicosanoids, and endothelin after liver transplantation.

Patients with hepatic cirrhosis develop widespread abnormalities in kidney function and vasoactive hormones. These change rapidly after liver transplantation during immunosuppression with cyclosporine. The role of changing eicosanoid excretion and endothelin levels in regulating renal function after transplantation in humans remains uncertain. We studied 32 patients with regard to renal hemodynamics, glomerular filtration, urinary prostacyclin (6-keto-PG-F1-alpha), thromboxane (TBX2), and endothelin before and during the first four weeks after orthotopic liver transplantation. Arterial pressure rose from 106 +/- 2/61 +/- 2 to 146 +/- 4/81 +/- 2 mmHg, (P less than .001), while renal blood flow fell (686 +/- 38 to 453 +/- 24 ml/min/1.73 m2, P less than .05), as did GFR. Pretransplant excretion of 6-keto and TBX2 was above that of normal subjects and fell progressively after transplant, as did plasma renin activity and aldosterone. The 6-keto levels fell below normal after two weeks. The ratio of TBX2/6-keto remained elevated compared with normal subjects throughout the month after transplant (1.54 +/- 0.38 vs. 0.54 +/- 0.07, P less than .01). Endothelin levels rose during the first week (7.4 +/- 1.4 vs. 12.4 +/- 2.7 pg/ml, P less than .05), but fell back to baseline thereafter. These results indicate that high levels of urinary eicosanoids in patients with liver disease fall rapidly after liver transplantation during CsA immunosuppression. Unlike results in many experimental models, these data suggest that renal vasoconstriction in humans may be associated primarily with suppression in renal prostacyclin excretion rather than stimulation of thromboxane.

Hepatitis G virus infection in patients transplanted for cryptogenic cirrhosis: red flag or red herring?

BACKGROUND: The significance of hepatitis G (HGV) infection in liver transplant recipients is not known. We set out to determine the pre-orthotopic liver transplantation (OLT) prevalence, the pre- and postoperative viral titers of HGV, and the allograft histology in patients infected with HGV who underwent OLT for cryptogenic cirrhosis. METHODS: HGV RNA was measured using a research-based branched DNA assay. The assay used a target-specific probe set that was based on the 5'-untranslated region of the HGV genome. Allograft histology was assessed with protocol liver biopsies in all patients who survived longer than 6 months. RESULTS: The preoperative prevalence of HGV infection in recipients transplanted for cryptogenic cirrhosis was 26%. Thirty-seven percent (12 of 33) of recipients who had serum available in the first postoperative month had HGV infection. Mean HGV RNA levels were 9.8 (+/-4.2) (viral molecular equivalents/ml x 10[6]) before OLT and 37.5 (+/-10.7) at 1 year after OLT. In 4 of the 11 cryptogenic recipients in whom HGV RNA was detectable in the first postoperative month, HGV RNA fell to undetectable levels at the most recent follow-up (mean 70 months). Of the five cryptogenic recipients who continue to have measurable HGV RNA, three have unexplained hepatitis histologically. CONCLUSIONS: These findings suggest the following: 1) The prevalence of HGV infection in patients undergoing OLT for cryptogenic cirrhosis is about 25%. 2) In recipients persistently infected with HGV, mean HGV RNA titers increase after OLT. 3) HGV RNA becomes undetectable in about one third of recipients who had detectable HGV RNA in the first month after OLT. 4) Hepatitis of uncertain etiology occurs in 60% (3 of 5) of persistently HGV-infected cryptogenic recipients.

Elevation of plasma endothelin associated with systemic hypertension in humans following orthotopic liver transplantation.

Endothelin (ET) is a 21-amino-acid peptide of endothelial origin, is a potent systemic and renal vasoconstrictor associated with sodium retention and modulation of the renin-angiotensin-aldosterone system. The present study was designed to determine if plasma ET is elevated in humans with cirrhosis (n = 12), a state characterized by sodium retention and increased plasma renin activity (PRA) and plasma aldosterone (PA), and to determine the effect of orthotopic liver transplantation (OLT) upon plasma ET, PRA, and PA at 1, 3, and 7 days after transplantation. Plasma ET before OLT was 1.62 +/- 0.23 pg/ml, which was not different as compared with normal controls. Plasma ET significantly increased to 4.18 +/- 0.66, 3.87 +/- 0.58, and 4.07 +/- 0.61 pg/ml, respectively following OLT. PRA remained elevated throughout the postoperative course, in contrast to PA that decreased following OLT. Mean arterial pressure increased significantly from 82 +/- 4 pre-OLT to 98 +/- 4 and 103 +/- 2 mmHG on days 3 and 7 respectively.

Immunohistologic labeling as an indicator of liver allograft rejection.

Monoclonal antibodies were used to identify T-helper cells (TH) and T-suppressor/cytotoxic cells (TS/C) in biopsy specimens obtained 7, 21, 90, 180, and 365 days postoperatively, and during episodes of graft dysfunction, from 34 consecutive liver transplant patients treated with cyclosporine and steroids. Rejection was diagnosed by the presence of appropriate laboratory and light microscopic findings and at least 8 weeks of follow-up to exclude other causes of graft dysfunction. Four immunohistologic patterns were seen--no labeled cells (No), only lobular TS/C, only portal TH, and a portal mixture of TH and TS/C (mix). Of 36 specimens with the No or only lobular TS/C pattern, 29 were not associated with rejection. Of the 39 specimens with the portal TH or portal Mix pattern, 33 were associated with a rejection episode. In addition, in nine specimens from patients with no biochemical or routine histologic evidence of rejection, the presence of portal TH or a portal mix indicated immunologic rejection 5 days to 5 weeks before biochemical and routine histologic evidence of it was manifested. Immunohistologic labeling appears to be an early indicator of liver allograft rejection.

Use of fatty donor liver is associated with diminished early patient and graft survival.

It is well known that implantation of donor livers with severe fatty infiltration (>60%) is frequently associated with early hepatic dysfunction and an increased incidence of primary nonfunction after liver transplantation. The outcome of donor livers with less fatty infiltration has not been well defined. We, therefore, studied the outcome of 59 liver transplantations in which donor livers with up to 30% fat were used. Patient outcome was compared to a time-matched control group of 57 patients. The two groups were similar in terms of age, gender, preservation time, primary diagnosis, and UNOS status. We compared both groups with regard to 4-month and 2-year patient and graft survival. We also assessed the incidence of ischemic type biliary strictures and hepatic artery thrombosis, and evaluated the causes of graft loss in both groups. We found that use of donor livers with up to 30% fatty infiltration was associated with a significant decrease in 4-month graft survival (76% vs. 89%, P<0.05) and in 2-year patient survival (77% vs. 91%, P<0.05). Primary nonfunction and primary dysfunction formed the main cause of graft loss and mortality. Multivariate analysis showed that fatty infiltration is an independent predictive factor for outcome after transplantation. We conclude that liver allografts with up to 30% fat lead to diminished outcome after liver transplantation. However, this diminished outcome should be viewed with respect to the increasing mortality on the national waiting list.

Role of steroid dose in hypertension early after liver transplantation with tacrolimus (FK506) and cyclosporine.

Transplant immunosuppression using either cyclosporine (CsA) or tacrolimus (FK506) leads to renal vasoconstriction and nephrotoxicity. Despite producing similar effects within the kidney and blood vessels, clinical hypertension occurs less frequently with tacrolimus during the first year after transplantation, compared with CsA. To examine the role of steroid dose in early posttransplant hypertension, we measured blood pressure and kidney function in liver transplant recipients treated with tacrolimus and either high-dose (TAC-HI-P, n = 19) or low-dose (TAC-LO-P,n = 20) prednisone, compared with CsA-treated recipients (n = 29) receiving prednisone doses similar to the TAC-HI-P group. At 1 month, hypertension occurred more often with CsA (72%) than with TAC-HI-P (42%, P < 0.05) or TAC-LO-P (30%, P < 0.05). By 4 months after transplantation, hypertension developed in nearly twice as many TAC-HI-P (63%) as TAC-LO-P patients (32%, P < 0.05), with no difference between TAC-HI-P and CsA (86%, NS). Daily prednisone dose at 1 month closely paralleled cumulative steroid dose in the first month in the TAC-HI-P and TAC-LO-P groups. Fourteen of 19 TAC-HI-P patients (74%) required bolus steroids for treatment of rejection within the first month, compared with 3/20 (15%) TAC-LO-P and 10/29 (34%) CsA recipients. Glomerular filtration rate fell from pretransplant levels at 1 month and 4 months to the same degree in CsA, TAC-HI-P, and TAC-LO-P patients. These results demonstrate a central role for steroid dose in the rate of onset of hypertension early after liver transplantation using tacrolimus immunosuppression. Both daily dose and cumulative dosage, including bolus treatment for rejection, may impact on the development of hypertension. Since prevalence rates rise to levels comparable to CsA by 24 months regardless of steroid dose, hypertension after liver transplant may be mediated by different mechanisms at different stages of the posttransplant course.

Do cold agglutinins have any impact on the outcome of liver transplantation?

Cold agglutinins, IgM red blood cell autoantibodies, cause cold agglutinin disease with hemolysis and microvascular occlusion. Cold preservation of kidneys during renal transplantation in the presence of cold agglutinins can cause graft malfunction. However, the impact of cold agglutinins on the outcome of liver transplantation is unknown. We measured the pretransplant presence and titer of cold agglutinins in 327 primary liver allograft recipients and analyzed their relationship to outcome after transplant. Thirty-three percent of pretransplant patients had cold agglutinins. Cold agglutinins were more common in patients with viral-related liver diseases (49%) compared with those with nonviral-related liver disease (32%). There was no difference between recipients with and without cold agglutinins in usage of blood products, postoperative day 2 aminotransferase levels, acute rejection at day 7, the development of hepatic artery thrombosis, nonanastomotic biliary strictures, or 4-month allograft survival. In conclusion, cold agglutinins are common in liver transplant patients before surgery, especially those with viral-related liver diseases. However, the presence of cold agglutinins does not impact on outcome after liver transplantation.

Neoral compared to Sandimmune is associated with a decrease in histologic severity of rejection in patients undergoing primary liver transplantation.

BACKGROUND: In a randomized, controlled study we investigated the clinical efficacy of the microemulsion formulation of cyclosporine (Neoral) in comparison with Sandimmune (SIM) in the treatment of patients who underwent primary orthotopic liver transplantation (OLT). METHODS: In total, 33 patients were randomized in a double-blind fashion before undergoing primary OLT to receive either Neoral or SIM. All 33 patients initially received intravenous cyclosporine, but as soon as it was tolerated, the oral study drug was initiated (median time, 3.6 days) and 17 patients received Neoral and 16 SIM (for both drugs, 10 mg/kg/day). Both groups were comparable with regard to age, sex, etiology of chronic liver disease, and hepatic biochemical profile. Episodes of rejection were diagnosed histologically and characterized as mild, moderate, or severe using criteria from the National Institute of Diabetes and Digestive and Kidney Diseases. RESULTS: Patients were followed for 1 year. Four patients in each group were discontinued prematurely. The reason for discontinuation of cyclosporine was drug-related complications in two of the NEO patients and in three of the SIM group; the other three were non-drug-related. Rejection episodes occurred in 9 of 17 patients (52.90%) in the Neoral group and in 9 of 16 patients (56.3%) in the SIM group. The total number of rejection episodes in each group was 14. However, in evaluating the severity of rejection histologically, nine episodes of rejection were characterized as moderate/ severe in the SIM group compared with only three in the Neoral group (P=0.027). Five of the nine moderate/severe rejection episodes in the SIM group occurred within the first 2 weeks after transplant. In contrast, moderate/severe rejection did not occur in the Neoral group in this early period. Two patients in the SIM group and no patients in the Neoral group required treatment with OKT3 for steroid-resistant rejection. There were no differences in mean doses or trough levels when comparing the two study groups. The incidence of adverse effects was similar in the two groups. CONCLUSIONS: Neoral is a safe and efficacious drug in the treatment of primary OLT patients. Given comparable doses of cyclosporine in each group over 1 year, there was no significant difference in the total number of rejection episodes between study groups. However, patients treated with Neoral had a lower incidence of moderate/severe histologic rejection and were free of steroid-resistant rejection when compared with SIM-treated patients.

The economic impact of cytomegalovirus infection after liver transplantation.

BACKGROUND: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients. METHOD: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed. RESULTS: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02). CONCLUSIONS: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.